Ferroptosis in Alzheimer’s Disease—Metabolism, Pathways, and Therapeutics: A Review

https://doi-001.org/1025/17667403114474

Jinzhou Song ¹, Jinying Pei ^1*

1   Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang Province, 150006, China

*  Jinying Pei: ashley2023lucky@163.com

Abstract

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. Currently, there is no cure for this disease, which is often ultimately fatal. Iron, as an essential trace element, is required for various physiological processes in the brain. However, imbalance in iron ions—whether excess or deficiency—proves detrimental and can lead to neuronal death through oxidative stress, ferroptosis, cellular senescence, or neuroinflammation. These processes have all been implicated in the pathological mechanisms of AD. Here, we review the physiological and pathological roles of ferroptosis, as it plays a dual role in maintaining cellular homeostasis and disease pathogenesis. We focus on elucidating the pathological mechanism of ferroptosis in AD and its upstream and downstream regulators. Subsequently, we summarize the currently targetable pathways regulating ferroptosis in AD treatment. Finally, we will discuss experimental studies on ferroptosis inhibitors for AD therapy. This comprehensive review of ferroptosis pathology in AD may facilitate the development of early diagnostic approaches and provide insights for future AD therapeutic strategies.

Keywords: Ferroptosis; Alzheimer’s disease; Signaling pathway; Iron homeostasis dysregulation; Lipid peroxidation

1. Introduction

The term ‘ferroptosis’ was formally coined in 2012 to describe an iron-dependent programmed cell death caused by abnormal accumulation of lipid peroxides on cell membranes.[1]During ferroptosis, mitochondria undergo significant morphological changes, including increased membrane density, reduction or disappearance of cristae, rupture of the outer mitochondrial membrane, loss of plasma membrane integrity, cytoplasmic swelling, and organelle enlargement.[2]Both apoptosis and necrosis possess distinct protein mechanisms mediating the execution steps of cell death, yet no proteins directly involved in executing ferroptosis have been identified. The occurrence of ferroptosis is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron metabolism, mitochondrial activity, amino acid metabolism, lipid metabolism, glucose metabolism, among others[3], exhibiting distinctive uniqueness compared to other forms of cell death. Ferroptosis exhibits a double-edged sword characteristic and may play a critical role in various physiological and pathological processes. On one hand, ferroptosis can activate immune responses by releasing damage-associated molecular patterns, suppress tumor growth, and participate in cell clearance and tissue remodeling during embryonic development. On the other hand, excessive ferroptosis can cause cellular damage and organ dysfunction, particularly in neurodegenerative diseases.[4]Ferroptosis plays a significant role in various human diseases (as shown in Figure 1). Understanding the mechanisms of ferroptosis facilitates the development of therapeutic approaches for related disorders. Previous studies have demonstratedthat ferroptosis may contribute to the pathological processes and pathogenesis of AD.[5]Experimental therapeutic agents targeting ferroptosis
inhibition have been shown to alleviate AD-related pathological alterations.

Figure 1. The role of ferroptosis in human diseases. This figure indicates that ferroptosis plays an important role in numerous human diseases. In metabolic disorders, ferroptosis can trigger obesity, diabetes, hyperlipidemia, and fatty liver disease. In genetic diseases, ferroptosis can impact thalassemia, Duchenne muscular dystrophy, and hereditary hemochromatosis. In cancer, ferroptosis primarily affects tumor growth, metastasis, invasion, and drug resistance. In neurological disorders, it participates in pain, brain and spinal cord injuries, cerebral infarction, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In musculoskeletal disorders, it causes sarcopenia, osteoarthritis, and osteoporosis. In autoimmune diseases, it primarily contributes to the pathogenesis of myasthenia gravis, rheumatoid arthritis, and systemic lupus erythematosus. In cardiovascular diseases, ferroptosis leads to heart failure, coronary artery disease, and myocardial ischemia-reperfusion injury.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by insidious onset, typically leading to cognitive decline, neuropsychiatric symptoms, and impaired activities of daily living.[6]Recent data indicate that dementia prevalence in Europe will double by 2050, while global prevalence will triple; these estimates become threefold higher when applying biologically-based definitions of AD.[7]The primary pathological hallmarks consist of two specific protein aggregates: senile plaques (SPs) formed by extracellular Aβ deposition in the cerebral cortex and hippocampus, and neurofibrillary tangles (NFTs) resulting from intracellular hyperphosphorylated tau protein accumulation in neurons.[8]Current understanding of AD pathology encompasses multiple hypotheses, including amyloid cascade, tauopathy, neuroinflammation, oxidative stress, metal ion dyshomeostasis, glutamate excitotoxicity, microbiota-gut-brain axis dysfunction, and aberrant autophagy, which collectively elucidate its underlying pathological mechanisms from diverse perspectives.[9]Evidence from human autopsies indicates that neuronal degeneration driven by iron overload and ferroptosis may constitute the initial stage of neuritic plaque formation, while neurofibrillary tangles represent remnants of iron-laden neurons formed independently of Aβ deposition.[10]Although regional iron dyshomeostasis, oxidative stress, and lipid peroxidation involved in ferroptosis play crucial roles in the pathogenesis of Alzheimer’s disease, the exact mechanisms remain incompletely understood. This review aims to elucidate the potential pathological mechanisms of ferroptosis in AD and its upstream/downstream regulators, summarize ferroptosis-related pathways implicated in AD research, and discuss the observed effects of ferroptosis inhibitors in experimental AD studies.

2. Involvement of Ferroptosis in AD Pathogenesis

Mounting evidence indicates a complex relationship between AD and ferroptosis, with both involving increased iron storage, reduced antioxidant capacity, and elevated lipid peroxidation (LPO).[11]Furthermore, neuroinflammation, oxidative stress, and neuronal damage resulting from ferroptosis processes can be observed in AD.[12]Recent evidence from human brain tissue indicates that Aβ correlates with activation of ferroptosis pathways in postmortem AD brain specimens. Notably, ferroptosis inhibition can block Aβ pathology, reduce lipid peroxidation, and restore iron storage in human AD iPSC-derived brain cortical organoids.[13]Additional studies suggest that the K677 mutation in Tau protein may influence ferritinophagy and ferroptosis through the MAPK signaling pathway. Reducing lactylation of tau K677 suppresses microglial activation and ameliorates cognitive function in AD mice.[14]Ferroptosis not only participates in the pathological process of Alzheimer’s disease (AD) but can also be regulated by various types of fibroblast growth factors, thereby influencing neuronal survival.[15]Studies indicate that iron overload in microglia reduces the secretion of insulin-degrading enzyme, which degrades Aβ. Consequently, this leads to extracellular Aβ accumulation and neurotoxicity.[16]Disruption of brain iron balance and neuronal ferroptosis can abnormally activate microglia, further promoting the release of inflammatory mediators. This exacerbates iron homeostasis dysregulation and intensifies neuroinflammation.[17]Research has found that droplet degeneration may participate in AD pathology, as Transferrin Receptor (TfR) is detectable on degenerating neurons exhibiting droplet degeneration. TfR both marks the onset of neuritic plaques and may serve as an early ferroptosis biomarker in AD pathogenesis.[18]Ferroptosis also influences AD progression by modulating neuroimmune-related cells (T cells, B cells, neutrophils, macrophages) and neural cells (glial cells and neurons).[19]Ca2+ homeostasis dysregulation is closely associated with AD pathology and can drive ferroptosis through multiple pathways, including interactions with iron and modulation of crosstalk between the endoplasmic reticulum (ER) and mitochondria.[20]In AD, various organelles including mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes participate in regulating ferroptosis through aspects of iron metabolism and redox imbalance.[21]Voltage-dependent anion channel 1 (VDAC1) protein in the mitochondrial outer membrane associates with mitochondrial dysfunction and ferroptosis. Activation of AMPK/mTOR and Wnt/β-catenin pathways alleviates Aβ1-42-induced damage in PC12 cells.[22]ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3), an endoplasmic reticulum-localized transmembrane protein, drives lipid peroxidation via the PERK-ATF4-HSPA5 pathway in AD models, directly promoting neuronal ferroptosis.[23]Recently, multiple research teams have elucidated the role of ferroptosis-related genes and molecular mechanisms in AD by integrating a series of bioinformatics techniques. They have identified several AD-associated ferroptosis genes, offering valuable references for drug development targeting ferroptosis in AD.[24]^,[25]^,[26]

2.1 Iron Metabolism in Ferroptosis Associated with AD

Iron is the most abundant essential trace element in the human body and plays a vital role in various physiological processes, including oxygen transport, DNA synthesis, mitochondrial respiration, and brain phospholipid synthesis.[27]Iron ions serve as essential cofactors for AD-related enzymes. Their homeostasis is regulated by multiple proteins and molecular mechanisms. Dyshomeostasis can readily trigger neuronal ferroptosis, thereby exacerbating AD progression.[28]Pericytes are crucial components of the brain’s neurovascular unit. Ferroptosis in pericytes can trigger structural alterations in the cerebral microvascular system, leading to blood-brain barrier disruption and extracellular matrix remodeling in Alzheimer’s disease.[29]AD-related pathological proteins, primarily Aβ and tau, can bind iron in multiple forms. Additionally, aging-associated pathological states in AD elevate iron levels, collectively heightening susceptibility to ferroptosis in Alzheimer’s disease.[30]Cerebral microhemorrhages have become a hallmark feature of AD, compromising the blood-brain barrier (BBB), exacerbating iron deposition and oxidative stress, thereby accelerating cognitive decline. Iron dysregulation, as a key driver of AD, can in turn exacerbate Aβ accumulation, tau hyperphosphorylation, and ferroptosis.[31]This clearly demonstrates that iron metabolism dysregulation triggers a vicious cycle with ferroptosis and AD, where each acts as both cause and effect. Genetic studies reveal that the long non-coding RNA (lncRNA) LINC00472 modulates iron accumulation in neuronal cells, thereby influencing ferroptosis in AD; moreover, levels of the ferroptosis-critical gene FOXO1 show positive correlation with AD severity.[32]Analysis of nearly 300,000 nuclei from parietal cortex cells of individuals carrying autosomal dominant AD genes (APP, PSEN1) and risk-modifying genes (APOE, TREM2, MS4A) demonstrated that APOEε4 suppresses neuronal function while exhibiting ferroptosis characteristics.[33]This mechanism of APOEε4 may involve promoting changes in the lipid composition of ferroptosis or reducing APOE levels. Conversely, the anti-ferroptotic mechanism of APOE operates through activation of the PI3K/AKT pathway, which inhibits ferritinophagy and prevents ferritin from releasing iron.[34]Additional data from AD patient brain tissues and peripheral blood demonstrate that SLC11A1 participates in AD progression by influencing ferroptosis and immune inflammation, as validated in ferroptosis models.[35]TFR1 is considered a marker protein for ferroptosis occurrence. Experimental knockout of TFR1 can inhibit ferroptosis, significantly alleviating oligodendrocyte inflammation and oxidative damage, thereby offering a potential therapeutic target for mitigating neurological damage and cognitive impairment.[36]DMT1 is a transmembrane transport protein responsible for transporting divalent iron ions within cells. In Aβ-overexpressing neurons of Caenorhabditis elegans, iron overload-induced ferroptosis alters the mitochondrial redox environment to drive oxidative damage. Knocking out DMT1 reduces neuronal uptake of Fe²⁺.[37]Ferroportin (Fpn) is an efflux transporter responsible for iron ion export in cells. Conditional knockout of Fpn in mice induces neuronal loss, brain atrophy, and cognitive impairment, exhibiting morphological and molecular features characteristic of ferroptosis.[38]These targets all play crucial roles in regulating iron metabolism.

2.2 Oxidative Stress Involvement in Ferroptosis in AD

Notably, effectors of antioxidant signaling cascades in ferroptosis exhibit reduced expression in neurons of AD patients. This indicates that redox imbalance during ferroptosis may constitute a key mechanism triggering AD pathology.[39]Glutathione (GSH), the most abundant and primary antioxidant in vivo, scavenges free radicals and neutralizes reactive oxygen species (ROS) and reactive nitrogen species (RNS). Research reveals a positive correlation between GSH levels in the brain and cognitive ability across different subjects. Reduced GSH levels in AD brains affect the content of advanced glycation end products and acrolein (a byproduct of lipid peroxidation).[40]The benefits of administering GSH via nebulization include enhanced NRF2 signaling pathway activation, improved mitochondrial function, and neuroprotection, constituting a promising intervention for Alzheimer’s disease.[41]GPX4 is a crucial antioxidant enzyme that reduces lipid peroxides using GSH, protecting neurons from oxidative damage, particularly by mitigating ferroptosis. Ferroptosis-related markers observed in 5xFAD mice include increased lipid peroxidation, elevated lysophospholipids, and reduced GPX4 levels. Conversely, Gpx4-overexpressing mice exhibit reduced neurodegeneration and ferroptosis marker levels through enhanced antioxidant capacity.[42]Studies found that overexpression of lactoferrin (Lf) in astrocytes can suppress Aβ production in APP/PS1 mice. This mechanism primarily inhibits neuronal ferroptosis by preventing GPX4 degradation and reducing intracellular iron accumulation.[43]ROS are oxidative molecules generated during cellular metabolism, such as superoxide anion (·O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radical (·OH). Excessive accumulation of ROS induces oxidative stress, damaging cells and tissues. NOX4 serves as a key source of ROS generation and can further exacerbate ferroptosis in AD astrocytes. Inhibition of NOX4 alleviates lipid peroxidation during ferroptosis, reduces Aβ and p-Tau levels, and mitigates mitochondrial abnormalities.[44]Furthermore, relevant oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), can mediate peroxidation of polyunsaturated fatty acid (PUFA) chains in membrane phospholipids, thereby disrupting membrane integrity during ferroptosis.[45]

2.3 Involvement of Lipid Metabolism in Ferroptosis within Alzheimer’s Disease

Related reports indicate that cognitive decline in elderly individuals correlates with low plasmalogen levels and elevated levels of lipid rafts, amyloid plaques, and neurofibrillary tangles in the temporal cortex.[46]Cellular vulnerability to ferroptosis involves multiple lipid metabolism pathways, including PUFA uptake and storage, synthesis and remodeling of PUFA-containing phospholipids, and monounsaturated fatty acid (MUFA) metabolism.[47]ACSL plays a unique role in fatty acid transport and metabolism. In 3xTg-AD mice, adenovirus-mediated overexpression of the ACSL3 gene elevates neurotrophic factor levels and alleviates AD-related depression and anxiety.[48]Lipid rafts are small, lipid-enriched microdomains within cell membranes, typically containing cholesterol, sphingomyelin, and specific membrane proteins. Research has found that lipid rafts in Alzheimer’s disease reduce antioxidant enzyme activity and increase oxidative damage; the associated neuronal loss may be related to lipid peroxidation, impaired antioxidant defenses, and ferroptosis signaling pathways. Iron chelation can reduce fibrillar amyloid deposition and lipid peroxidation while enhancing glutathione (GSH)-mediated antioxidant effects.[49]This experiment verifies the hypothetical role of ferroptosis in AD pathology. In microglia within the white matter of AD patients’ brains, myelin fragments with impaired phagocytic function can be destroyed by iron-rich myelin debris and undergo ferroptosis, exhibiting lipid peroxidation damage and mitochondrial oxidative stress.[50]This appears to be the primary mechanism underlying white matter damage and myelin loss in the AD brain. APOE is a major cholesterol carrier mediating lipid transport in the brain. A recent case report described a homozygous carrier of the APOE3 Christchurch (APOECh) mutation who exhibited resistance against autosomal dominant AD caused by the PSEN1-E280A mutation.[51]Further research revealed that in induced pluripotent stem cell (iPSC)-based AD models, APOECh microglia demonstrated resistance to Aβ-induced lipid droplet formation, lipid peroxidation, and ferroptosis, consequently retaining phagocytic activity and promoting pTau clearance.[52]

In summary, we can confirm that ferroptosis constitutes a crucial component in AD, offering a novel pathological mechanism. Due to its unique biochemical and genetic foundations, ferroptosis presents a new therapeutic avenue for AD treatment. Although AD drug development faces numerous challenges—such as complex pathogenesis, irreversible disease progression, difficulties in penetrating the blood-brain barrier, and clinical trial hurdles—therapeutic strategies targeting ferroptosis have yielded some promising results, providing valuable insights for AD prevention and treatment.

3. Major Signaling Pathways Regulating Ferroptosis in AD

With in-depth research on ferroptosis mechanisms, growing evidence indicates that ferroptosis holds significant implications in preclinical studies of Alzheimer’s disease. For instance, Aflatoxin B1 (AFB1) can disrupt redox homeostasis and activate the SLC7A11/GPX4 signaling pathway of ferroptosis to induce AD-like pathological features.[53]Chronic noise exposure can induce AD-like neuropathological alterations and cognitive impairment in rat hippocampus, leading to changes in ferroptosis-related markers.[54]The aforementioned studies clearly demonstrate that ferroptosis may contribute to the pathogenesis of Alzheimer’s disease. Furthermore, ferroptosis can be regulated by multiple genes and, through various signaling pathways, induces iron overload, lipid peroxidation, disruption of redox homeostasis, and reactive oxygen species accumulation, thereby exacerbating the pathological progression of AD.[55]In recent years, both cell line and animal studies applying ferroptosis modulators to AD treatment have yielded encouraging results.[56]In an AD cell model with stable APP overexpression, Oleanonic acid (OA) reduces neuronal damage by activating the Nrf2/HO-1 signaling pathway, thereby suppressing oxidative stress, autophagy defects, ferroptosis, mitochondrial damage, and endoplasmic reticulum stress.[57]As a gut-brain hormone, ghrelin ameliorates ferroptosis-related proteins and metabolic markers via the BMP6/SMAD1 pathway. It inhibits microglial ferroptosis to promote M2 polarization, mitigates mitochondrial structural damage, and thereby alleviates neuroinflammation and plaque deposition.[58]Sennoside A (SA) ameliorates cognitive function, reduces hippocampal neuron apoptosis, ferroptosis, oxidative stress, and neuroinflammation in APP/PS1 mice, while suppressing AD-induced overexpression of TRAF6 and p-P65.[59]A team innovatively integrated gallic acid with cyclic dipeptides to synthesize the small molecule GCTR—capable of simultaneously targeting ferroptosis and amyloid toxicity in AD. This compound enhances GPX4 activity and regulates Fe³⁺-induced liquid-liquid phase separation (LLPS) of tau protein.[60]The above evidence indicates that multiple signaling pathways involved in ferroptosis may participate in AD pathology. Therefore, in this section, we summarize the molecular mechanismsof different ferroptosis signaling pathways in AD.

3.1 System Xc-(SLC7A11)/GSH/GPX4

The cystine/glutamate antiporter (System Xc⁻) is an amino acid transporter composed of SLC7A11 (xCT) and SLC3A2 (4F2hc) subunits. It mediates the 1:1 transmembrane exchange of intracellular glutamate for extracellular cystine, exhibiting antioxidant properties and regulating neural signal transmission.[61]Studies reveal that upregulation of System Xc- enhances cystine uptake and subsequent elevation of cysteine levels, promoting GSH production and glutathione peroxidase (GPX) activity. This represents a mechanism through which aging neurons protect themselves against ferroptosis.[62]However, glutamate efflux as an alternative release pathway may also induce excitotoxicity. Research indicates that Aβ25-35 can upregulate System Xc- expression, leading to increased glutamate release from astrocytes and NMDA receptor activation. This converts oxidative stress into excitotoxicity, ultimately triggering neuronal death in Alzheimer’s disease.[63]As a key upstream regulator of ferroptosis, SLC7A11 transports cystine into cells where it is reduced to cysteine for glutathione synthesis and antioxidant defense.[64]Glutathione (GSH), synthesized through the conjugation of glutamate, cysteine, and glycine catalyzed by GCLC and GSS, functions as an antioxidant. It reduces ROS and RNS under GPX catalysis, thereby maintaining redox homeostasis and mitigating xenobiotic toxicity. Glutathione peroxidase 4 (GPX4), the fourth member of the selenium-containing GPX family, serves as the core antioxidant defense enzyme against ferroptosis. It primarily catalyzes the conversion of GSH to oxidized glutathione (GSSG) while reducing cytotoxic lipid hydroperoxides (L-OOH) to their corresponding alcohols (L-OH), thereby preventing ferroptosis.[65]GSSG is reduced back to GSH by glutathione reductase (GR) utilizing NADPH.

Studies reveal that regular aerobic exercise improves learning and memory in APP/PS1 mice, upregulating the Xc-/GPx4 pathway in the prefrontal cortex, thereby reducing AD-induced ferroptosis.[66]Research specifically addressing how exercise affects ferroptosis in the AD brain identified differentially expressed ferroptosis-related genes in the hippocampus, including hub genes such as SLC2A1, TXN, MEF2C, and KRAS, suggesting exercise may enhance antioxidant defense and regulate iron metabolism through Nrf2.[67]In Al(mal)3-induced PC12 cells, ferroptosis was triggered through activation of the oxidative damage signaling pathway, manifested by inhibition of system Xc−, leading to cellular GSH depletion and glutathione peroxidase inactivation, ultimately resulting in ROS accumulation.[68]Biochanin A effectively inhibits glutamate-induced ferroptosis in mouse hippocampal neurons, reduces intracellular iron accumulation and lipid peroxidation, and modulates GPX4 levels by regulating its autophagic-dependent degradation.[69]Studies have found that frataxin (FXN)-mediated ferroptosis may represent a potential mechanism leading to Alzheimer’s disease (AD). FXN overexpression prevents L-glutamate (L-Glu)-induced ferroptosis in SH-SY5Y cells by activating the system Xc-/GSH/GPX4 pathway, achieved through suppression of ACSL4 and TfR1 protein expression.[70]

3.2 Iron Metabolism Pathway

As an essential trace element in humans, iron plays crucial physiological roles in oxygen transport, DNA synthesis, mitochondrial respiration, and phospholipid synthesis.[71]When iron crosses the blood-brain barrier and blood-cerebrospinal fluid barrier into the brain, it participates in neuronal development, myelination, and neurotransmitter synthesis.[72]Although iron is essential for neuronal homeostasis, iron overload increases ferroptosis. A key trigger of this process is the excessive accumulation of intracellular Fe²⁺, which promotes the Fenton reaction, leading to oxidative stress and free radical generation that damages cells by destroying proteins, lipids, and DNA.[73]Elevated iron levels in the brain can trigger ferroptosis and contribute to the development of various neurodegenerative diseases such as AD, PD, and HD.[74]A large cohort study observed that brain iron levels are closely associated with cognitive decline.[75]Furthermore, the severity of ferroptosis in AD patients’ brains depends on glial cell activation.[76]Among various cell types in the central nervous system, ferroptosis in microglia is closely associated with AD, as these cells serve as primary sites for iron accumulation and storage.[77]A murine study revealed that chronic iron exposure induces neuronal loss through apoptosis, autophagy, and ferroptosis, thereby elevating AD risk.[78]Aberrant phosphorylation of Tau and APP constitutes a key pathological hallmark of AD. Dysregulated iron metabolism influences the expression of kinases including GSK3β, CDK5, and MAPK. This activates pathways such as PI3K/AKT/GSK3β, MAPK/P38/HIF-1, and PKC/IRP1, forming a complex phosphorylation network that promotes Tau hyperphosphorylation and contributes to AD pathological mechanisms.[79]Collectively, iron metabolism in organisms can be linked and regulated through multiple signaling pathways, including the transferrin (TF)/transferrin receptor (TFRC) pathway, hepcidin (Hepc)/ferroportin (FPN1) pathway, and iron regulatory protein (IRP)/iron-responsive element (IRE) pathway. Concurrently, numerous key molecules participate in regulating cellular iron homeostasis and ferroptosis, such as divalent metal transporter 1 (DMT1/SLC11A2), ferritin heavy chain 1 (FTH1), ceruloplasmin (CP), and prostate six-transmembrane epithelial antigen 3 (STEAP3).[80]

Studies have found that downregulation of calcium/calmodulin-dependent protein kinase II (CaMKII) in the AD cortex may disrupt TF/TFRC signaling, leading to iron overload and neurodegeneration through iron-induced toxicity.[81]Overexpression of Hepc in astrocytes acts upon FPN1 (SLC40A1) on brain microvascular endothelial cells, reducing cerebral iron levels in APP/PS1 mice while decreasing oxidative stress and neuroinflammation.[82]In rats with cognitive impairment induced by intraperitoneal STZ injection, SLC40A1-mediated iron overload and ferroptosis were found to potentially play significant roles in the pathogenesis.[83]One characteristic feature of AD is increased Aβ deposition resulting from abnormal cleavage of APP. Given Aβ’s strong affinity for iron, iron influx can drive translational expression of neuronal APP. This process is closely associated with interactions between IREs in the 5′-untranslated region (5′-UTR) of APP mRNA and IRP1.[84]Furthermore, novel therapies targeting IREs in APP mRNA have demonstrated promising outcomes in AD treatment.[85]Research on iron-related genetic loci in blood samples from participants in the Memory and Aging Project revealed close connections between circadian rhythms, mitochondria, and iron regulatory pathways, while also indicating distinct homeostatic regulatory mechanisms may exist between systemic organs and the brain.[86]As a form of physical therapy, electromagnetic fields (EMF) have been widely applied to enhance neurological function and promote injury repair. EMF can regulate the progression of neurological disorders by modulating iron metabolism through adjustments in membrane structure/function, ion channels, and ROS production.[87]Given the disruption of iron homeostasis in AD, plasma hepcidin may serve as a potential informative biomarker for Alzheimer’s disease.[88]Ferritin is composed of light chains (FTL) and FTH1. It not only mediates iron storage and transport but also limits ROS formation, thereby mitigating damage to cellular structures.[89]Studies have reported that decursin can upregulate FTH1 to regulate cellular iron homeostasis by promoting Nrf2 translocation into the nucleus of SH-SY5Y neuroblastoma cells, thereby alleviating glutamate-induced neurotoxicity and inhibiting ferroptosis.[90]

3.3 Lipid Peroxidation Signaling Pathway

Lipid peroxidation is defined as the oxidative degradation of lipids, particularly those containing carbon-carbon double bonds such as polyunsaturated fatty acids (PUFAs), especially arachidonic acid (AA), adrenic acid (AdA), and α-eleostearic acid (α-ESA), rendering cells susceptible to ferroptosis. This process is mediated by reactive oxygen species (ROS) and propagates through chain reactions involving lipid free radicals.[91]During ferroptosis, multiple enzymes play critical roles in catalyzing lipid peroxidation: acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) mediate PUFA-phospholipid (PUFA-PL) synthesis, while arachidonate lipoxygenases (ALOXs) and cytochrome p450 oxidoreductase (POR) catalyze PUFA-PL peroxidation. Lipid peroxidation serves as the ultimate executor inducing cellular damage and ferroptosis, with its peroxidation products including lipid hydroperoxides (LOOH), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE).[92]Metabolism of biological lipids may regulate ferroptosis by controlling phospholipid peroxidation and various related cellular processes. Pathways linking lipid metabolism to ferroptosis include PI3K-AKT-mTOR, LKB1-AMPK, YAP/TAZ, and VHL-hypoxia-inducible factor (HIF).[93]AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, regulates ferroptosis by phosphorylating substrates. When its key target acetyl-CoA carboxylase (ACC1) is inhibited, AMPK reduces free fatty acids—particularly polyunsaturated fatty acids (PUFAs). Furthermore, AMPK promotes fatty acid oxidation and enhances NADPH and GSH levels, which are essential for preventing ferroptosis.[94]Other cellular energy sensors, including peroxisome proliferator-activated receptors (PPARs) and transcription factor EB (TFEB), can also modulate the progression of ferroptosis in Alzheimer’s disease by regulating autophagy.[95]

Previous studies have demonstrated that dysregulation of cholesterol, sphingolipid, and glycerophospholipid metabolism directly exacerbates AD progression by stimulating Aβ deposition and Tau protein tangles. A series of drugs targeting abnormal lipid metabolism for AD treatment have demonstrated positive therapeutic effects.[96]A research team implemented genome-wide CRISPR-Cas9 screening and determined that the level of the distal cholesterol synthesis pathway intermediate metabolite 7-DHC directly influences cellular susceptibility to ferroptosis. They identified MSMO1, CYP51A1, EBP, and SC5D as potential ferroptosis suppressors, while DHCR7 acts as a pro-ferroptosis gene.[97]Studies have revealed that treatment with *Bacteroides ovatus* or its associated metabolite lysophosphatidylcholine (LPC) significantly reduces Aβ burden and ameliorates cognitive impairment. Mechanistically, LPC acts through the G protein-coupled receptor (GPR119) to suppress ACSL4 expression, thereby inhibiting ferroptosis and ameliorating AD pathology.[98]Insamgobonhwan (GBH) possesses antioxidant properties. In vivo experiments demonstrated that GBH improved cognitive impairment in mice and inhibited Aβ-induced lipid peroxidation. In the RSL3-induced ferroptosis model using HT22 cells, GBH restored the expression of ferroptosis marker proteins such as GPX4, HO-1, and COX-2, while suppressing cell death and lipid peroxidation.[99]ALDH2 is primarily localized in mitochondria and cytoplasm, participating not only in ethanol metabolism but also serving as a crucial mediator in the redox reactions of endogenous aldehyde products released during lipid peroxidation. Research has demonstrated that aldehyde dehydrogenase 2 family member (ALDH2) can ameliorate cardiac systolic dysfunction in APP/PS1 mouse models of AD by regulating lipid peroxidation and inhibiting ACSL4-dependent ferroptosis.[100]

3.4 FSP1-CoQ10-NAD(P)H Signaling Pathway

Research indicates a potential ferroptosis suppression system parallel to the GPX4 pathway. In 2019, the research team identified a novel anti-ferroptosis gene—ferroptosis suppressor protein 1 (FSP1), originally named apoptosis-inducing factor mitochondria-associated 2 (AIFM2)—in GPX4-deficient cells. FSP1 primarily localizes to lipid droplets and membranes.[101]Functioning as an NAD(P)H-dependent oxidoreductase, FSP1 reduces CoQ10 to CoQ10(H2), thereby inhibiting lipid peroxidation (LPO) and halting the ferroptotic lipid peroxidation chain reaction through capturing lipid peroxidation free radicals (LOO·). FSP1 can also inhibit ferroptosis by activating ESCRT-III-dependent membrane repair.[102]CoQ10, functioning as a lipid antioxidant and electron transporter in the mitochondrial electron transfer system, primarily exists in three forms: oxidized form—ubiquinone, reduced form—ubiquinol, and semi-oxidized form—semiquinone. Only the reduced form ubiquinol CoQ10(H2) can restore impaired mitochondrial function in AD by regulating the oxidative phosphorylation system, which can serve as both an antioxidant and free radical scavenger, thereby preventing oxidative damage to lipids, proteins, and nucleic acids.[103]NADH is abundantly present on the cell membrane, primarily generated by aldehyde dehydrogenase 7A1 (ALDH7A1). ALDH7A1 can directly reduce lipid peroxidation by consuming reactive aldehydes, and activate AMP-activated protein kinase (AMPK) to promote the recruitment of FSP1 on the membrane.[104]NADPH oxidase 4 (NOX4) is a ROS-producing membrane protein; NOX4 may play roles in activating reactive astrocytes, inducing astrocyte ferroptosis, and contributing to neuronal tau pathology during Alzheimer’s disease.[105]

In both in vivo and in vitro experiments, anthocyanins demonstrate significant neuroprotective effects by effectively inhibiting neuronal ferroptosis and alleviating oxidative stress through dual regulation of the FSP1 and xCT/GPX4 pathways.[106]In the lipopolysaccharide (LPS)-induced cognitive impairment model, insulin treatment alleviated LPS-induced cognitive decline, promoted the phosphopentose pathway (PPP) and NADPH production, and reduced mitochondrial damage and lipid peroxidation associated with hippocampal ferroptosis through activation of the GSH-GPX4 pathway.[107]Previous studies have confirmed that CoQ10 can improve learning and memory deficits caused by Alzheimer’s disease (AD).[108]Further research revealed that CoQ10 treatment dose-dependently mitigated oxidative damage, neuroinflammation, and Aβ levels in Wistar rats; it also enhanced cholinergic and neurotrophic drivers, effectively ameliorating memory impairment induced by nicotine-ethanol withdrawal.[109]Furthermore, the CoQ10 analog idebenone (IDB) may inhibit ferroptosis and neuroinflammation by enhancing FSP1 protein stability through N-myristoyltransferase (NMT)-mediated N-myristoylation, thereby improving recovery from early brain injury induced by subarachnoid hemorrhage in aged mice.[110]Diosgenin can restore memory function in AD model mice through SPARC-driven axonal growth.[111]Additionally, regulating both the FSP1/CoQ10 pathway of the ferroptosis defense system and the ACSL4/LPCAT3/ALOX15 pathway of the ferroptosis execution system can alleviate lipid metabolism disorders in rats.[112]

3.5 GCH1-BH4-DHFR Signaling Pathway

GTP cyclohydrolase 1 (GCH1) regulates nitric oxide (NO) activity, thereby controlling blood pressure, vasodilation function, and oxidative stress. Deficiency in GCH1 limits tetrahydrobiopterin (BH4) synthesis, leading to neuropsychiatric disorders such as Parkinson’s disease (PD) and depression.[113]BH4 is a critical enzymatic cofactor required for the synthesis of serotonin (5HT), dopamine (DA), and nitric oxide (NO). It further participates in multiple physiological processes in both peripheral and central systems, including vascular formation, neuroinflammation, glucose homeostasis, oxidative stress regulation, and neurotransmission.[114]De novo synthesis of BH4 initiates from guanosine triphosphate (GTP) and involves the sequential activation of three enzymes: GCH1, 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR). GCH1 serves as the rate-limiting enzyme that mediates the conversion of dihydrobiopterin (BH2) to BH4 by dihydrofolate reductase (DHFR).[115]Studies report that GCH1 overexpression promotes BH4/BH2 biosynthesis and selectively protects specialized phospholipids containing bis-polyunsaturated fatty acyl tails from peroxidative damage. BH4 acts as a radical-trapping antioxidant that eliminates CoQ10-associated lipid peroxidation and ferroptosis by interfering with the synthesis of CoQ10 precursors through disrupting phenylalanine-to-tyrosine conversion.[116]Although BH4 can function as an anti-inflammatory molecule and free radical scavenger, it is prone to auto-oxidation in the presence of molecular oxygen, leading to the release of superoxide radicals and thereby promoting inflammatory processes. Alterations in BH4 levels occur in numerous pathological conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and depression, involving increased oxidative stress, neuroinflammation, and monoaminergic dysfunction.[117]

BH4 maintains membrane stability and prevents cell membrane rupture characteristic of ferroptosis by inhibiting the accumulation of phospholipid hydroperoxides (PLOOH). Simultaneously, BH4 serves as an essential cofactor for endothelial nitric oxide synthase (eNOS). Its deficiency leads to eNOS uncoupling, producing superoxide anions (O₂⁻) instead of nitric oxide (NO). Normal NO production activates the sGC-cGMP-PKG pathway, suppressing ROS accumulation and ferroptosis.[118]A whole-genome sequencing study of AD in the Chinese population revealed that risk variants in the APOE, GCH1, and KCNJ15 loci may influence AD by regulating immune-related pathways.[119]Further investigations utilizing genome-wide association studies and next-generation sequencing technology identified AD risk-associated genetic loci, including KCNJ15, TREM2, and GCH1.[120]Analysis of circular RNA levels in AD patients demonstrated that Circ_0001535 possesses the highest diagnostic value for AD; acting through the E2F transcription factor 1 (E2F1)/DHFR axis, it reduces cell proliferation and promotes apoptosis.[121]When 3xTg-AD mice received consecutive 10-day BH4 treatment (15mg/kg), cognitive and metabolic deficits in Alzheimer’s disease were improved, but no significant effect was observed on Aβ and tau neuropathology.[122]C1q/TNF-related protein 13 (CTRP13), a secreted adipokine, ameliorates mitochondrial oxidative stress by activating the GCH1/BH4 signaling pathway, upregulates the ferroptosis-protective protein GPX4, reduces ACSL4 levels, and inhibits endothelial cell ferroptosis.[123]Dietary folic acid supplementation significantly alleviates aortic valve calcification in hypercholesterolemic Apoe-/- mice by increasing DHFR and rescuing BH4 biosynthesis.[124]Therefore, the GCH1-BH4-DHFR pathway may play a role in ferroptosis in Alzheimer’s disease, though specific mechanistic studies remain relatively scarce.

3.6 NRF2

Nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) is a key transcription factor regulating oxidative stress. Nearly all genes involved in ferroptosis—including GSH regulatory genes (GCLC, GCLM, GSR, GSS, SLC7A11, GPX4), NADPH regeneration genes (NOQ1), and iron regulatory genes (FTL, FTH1, FPN1, HO-1, SOD2)—are transcriptionally regulated by NRF2.[125]Studies indicate that Nrf2 and its target genes progressively decrease with advancing age, consistent with increased iron-mediated cell death. Both mechanisms contribute to the pathogenesis of neurodegenerative diseases (NDs).[126]Under oxidative stress conditions, Nrf2 dissociates from Keap1 and translocates into the nucleus, where it forms heterodimers with sMaf transcription factors and binds to antioxidant response elements (ARE), thereby triggering the expression of downstream antioxidant enzymes.[127]Reduced Nrf2 levels have been observed within hippocampal neurons in Alzheimer’s disease, potentially attributable to GSK3β hyperactivation, elevated MAFF homodimers, and increased BACH1 expression. Enhancing NRF2 signaling to counteract neuronal ferroptosis represents a promising therapeutic target for mitigating neuron loss in Alzheimer’s disease.[128]The hallmark pathologies of Alzheimer’s disease involve abnormal aggregation of specific proteins, such as Aβ plaques and P-tau. Imbalances in proteostasis may impair NRF2 activity through mechanisms involving the unfolded protein response (UPR), ubiquitin-proteasome system (UPS), and autophagy.[129]E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) are key enzymes in the UPS, with mounting evidence highlighting their roles in regulating ferroptosis in Alzheimer’s disease.[130]Activation of the Nrf2 pathway reduces phosphorylated tau (p-tau) levels by inducing the autophagy adaptor protein NDP52 in neurons.[131]

miRNAs are a class of non-coding small RNA molecules that regulate gene expression by binding to specific target messenger RNAs (mRNAs). Studies have confirmed that the expression of specific miRNAs modulates IGFBP-2 and neuronal ferritin expression, disrupts key genes in the Nrf2/SLC7A11/GPX4 pathway, impairs antioxidant enzyme activity and elevates oxidative stress levels. This exacerbates the progression of Alzheimer’s disease and ferroptosis, while inducing significant increases in neuroinflammation and GFAP.[132]BACE1 serves as the rate-limiting enzyme for Aβ generation. Activation of Nrf2 reduces the production of BACE1 and BACE1-AS transcripts, decreases Aβ formation, and ameliorates cognitive deficits in animal models of Alzheimer’s disease.[133]Superoxide dismutase 2 (SOD2), an antioxidant enzyme within mitochondria also regulated by NRF2, eliminates superoxide anions (O₂⁻) to maintain cellular redox homeostasis. Studies reveal that trehalose exerts neuroprotective effects by activating the SIRT3/SOD2 pathway, thereby reducing neuronal apoptosis and suppressing ferroptosis.[134]Nrf2/Bach1 target genes have emerged as crucial defenders in anti-ferroptosis pathways. A combined approach of activating Nrf2 while inhibiting Bach1 synergistically regulates oxidative stress, neuroinflammation, and ferroptosis processes in Alzheimer’s disease (AD).[135]Novel cannabidiol (CBD) derivatives can simultaneously inhibit BACH1 and activate NRF2, demonstrating neuroprotective effects in relevant cellular models.[136]Loss of blood-brain barrier (BBB) integrity is closely associated with Alzheimer’s disease. NRF2 activation contributes to mitigating oxidative stress and neuroinflammation while also regulating tight junctions and matrix metalloproteinases.[137]

4. AD Treatment Strategies Targeting Ferroptosis

Substantial preclinical research data indicate that molecular mechanisms related to ferroptosis are closely associated with AD, and targeting ferroptosis may represent a viable approach for the prevention and treatment of AD.[138]Currently, commonly used ferroptosis inhibitors include: Ferrostatin-1 (Fer−1), Liproxstatin-1 (Lip−1), α-tocopherol (Vitamin E), Zileuton, Ferroptosis suppressor protein 1 (FSP1), Coenzyme Q10 (CoQ10), and Tetrahydrobiopterin (BH4) which block the lipid peroxidation cascade; as well as Deferoxamine (DFO), Deferiprone (DFP), and N-acetylcysteine (NAC) that target other cellular pathways.[139]However, most ferroptosis inhibitors have not yet been translated into clinical use, facing numerous challenges including low oral bioavailability, difficulty penetrating the blood-brain barrier, poor safety profiles, drug side effects, lack of clinical trial data, and insufficient understanding of their mechanisms of action and targets. Therefore, it is imperative to evaluate the latest experimental data from this research field to seek optimal therapeutic strategies. Here we summarize recent studies on relevant ferroptosis inhibitors as potential Alzheimer’s disease therapies (as shown in Table 1).

Table 1. This table presents recent experimental studies of ferroptosis-related pathways in AD.

Compound	Source /Compose	Experimental model				Positive drug	Signaling pathways
		In vitro	Dosage	In vivo	Dosage
Berberine[140]	Coptis chinensis	SH-SY5Y cells	10、20、40 μg/mL	5xFAD mice	100mg/kg	—	JNK/P38MAPK
Berberine [141]	Coptis chinensis	N2a-sw cells	1、2.5、5、10、15μM	3×Tg-AD mice	50mg/kg	Fer-1(1、2、4、8μM)、RSL3(1μM)、ML385(20μM)	SLC7A11/GSH/GPX4
ganoderic acid A[142]	Ganoderma lucidum	HT22 cells	20、50、100 μM	APP/PS1mice	25、100 mg/kg	Donepezil(0.65 mg/kg)	NRF2/SLC7A11/GPX4、AMPK/GSK3 β/Nrf2、Keap1-Nrf2
Saponins from Astragalus membranaceus[143]	Astragalus membranaceus	HT22 cells	50、100 μ g/mL	SAMP8 mice	200、400、800 mg/kg	Donepezil(1 mg/kg) ferrostatin-1(5 mg/kg)	NOX4/Nrf2
Lignans of Schisandra chinensis[144]	Schisandra chinensis	HT22 cells	7.5、30 μg/mL	SAMP8 mice	100、200mg/kg	Donepezil(1 mg/kg) ferrostatin-1(5 mg/kg)	Nrf2/FPN1
Hederagenin[145]	Ivy seeds	HT22 cells	0.1 μM	—	—	GW6471(10 μM)	PPARα/Nrf2/GPX4
Catalpol[146]	Rehmannia glutinosa	—	—	APP/PS1 mice	5 mg/kg	—	HSPA5/GPX4
Avicularin[147]	Zanthoxylum bungeanum Maxim	SH-SY5Y cells	100 μM	APP/PS1 mice	12.5、25、50 mg/kg	Donepezil(5 mg/kg) Huperzine A (50μM)	NOX4/Nrf2
Thonningianin A[148]	Thonningia sanguinea	PC-12 cells、SH-SY5Y cells	8 μM	C. elegans models	20 μM	—	AMPK/Nrf2/GPX4
Salidroside[149]	Rhodiola Rosea L.	—	—	SAMP8 mice	30、60mg/kg	ferrostatin-1(5 mg/kg)	Nrf2/GPX4
Salidroside [150]	Rhodiola Rosea L.	HT22 cells	40 μM	Nrf2−/−AD mice	50mg/kg	Fer-1 (5μM)	Nrf2/HO-1
Eriodictyol[151]	in the peel of citrus fruits	HT-22 cells	0、2、4、8 μM	APP/PS1 mice	50 mg/kg	—	Nrf2/HO-1
Schisandra total lignans[152]	Schisandra chinensis	SH-SY5Y cells	0.5、1.5 μ g/ml	3xTg-AD mice	25、50 mg/kg	—	NADK/NADPH/GSH
Tetrahydroxy stilbene glycoside[153]	Polygonum multiflorum	—	—	APP/PS1 mice	60、120、180 mg/kg	—	GSH/GPX4/ROS、Keap1/Nrf2/ARE
Emodin[154]	Rhubarb	PC-12 cells	2.5、5、10 μM	—	—		Nrf2/GPX4 TLR4/p-NF-κB/NLRP3
Artemisinin[155]	Artemisia annua	HT22 cells，SH-SY5Y cells	5 μM、10 μM	3×Tg-AD mice	5、10 mg/kg	Ferrostatin-1(10 μM)	Nrf2-SLC7A11-GPX4
Water extract of Moschus[156]	Moschus	HT22 cells	30 μg/ml、60 μg/ml	—	—	Fer-1(15μ M)、ML385(10 μM)	Keap1/Nrf2
Schisandrin B[157]	Schisandra chinensis	SH-SY5Y/APP695swe cell	5、10、20 μM	3×Tg mice	25、50 mg/kg	Donepezil(1mg/kg)	GSK3β/Nrf2/GPX4
Curculigoside[158]	Curculigo	SH-SY5Y cell	3.125 μM、12.5μM	ICR mice	12.5、25、50、100mg/kg	Erastin(10 μM)、RSL3(2 μg/mL)	SLC7A11/GPX4
Ginkgolide B[159]	Ginkgo biloba	—	—	SAMP8 mice	20、30、40mg/kg	RSL3(100mg/kg)	Nrf2/GPX4
Neuritin[160]	—	HT22 cell	1μg/ml	APP/PS1 mice	5μg/μL	LY294002(10μM)	PI3K/Akt
Cerebroprotein hydrolysate-I[161]	pig brain tissue	—	—	APP/PS1 mice	20 mg/kg	—	p53/SAT1/ALOX15
Dexmedetomidine[162]	—	—	—	C57BL/6 mice	20 μg/kg	—	mTOR/TFR1

5. Summary

AD is the most prevalent form of dementia in the elderly, characterized as a neurodegenerative disorder of the central nervous system featuring progressive cognitive impairment and behavioral deficits. The definitive etiology leading to neuronal death and degeneration in Alzheimer’s disease remains unidentified. Current understanding of its pathogenesis involves complex mechanisms including the Aβ hypothesis, p-Tau hypothesis, neuroinflammation hypothesis, mitochondrial dysfunction, cholinergic hypothesis, oxidative stress, ferroptosis, and gut microbiota dysbiosis. Currently, AD therapeutic drugs approved by the China Food and Drug Administration include memantine, rivastigmine, galantamine, and donepezil. Although these drugs may exert therapeutic effects through the synergistic actions of multiple mechanisms, they remain unable to completely halt the pathological progression of AD and frequently exhibit certain side effects. Therefore, research on the pathogenesis of AD is crucial for identifying novel targets for drug development. In recent years, researchers have been investigating the pathological mechanisms of ferroptosis, including dysregulation of iron homeostasis, disorders of lipid metabolism, and imbalances in amino acid metabolism—all of which are associated with neuronal damage in AD. It is therefore necessary to further study the specific mechanisms of ferroptosis and related signaling pathways to enhance our understanding of AD pathogenesis. In this review, we briefly discuss the involvement of ferroptosis in human physiological and pathological processes, summarize current research perspectives on ferroptosis in AD, and highlight how the implicated pathways may serve independently or synergistically as biomarkers or therapeutic targets for AD. This paper also summarizes recent experimental drugs that alleviate AD by inhibiting ferroptosis. Future research should further elucidate the multifaceted mechanisms through which these drugs inhibit ferroptosis, identify specific targets within the ferroptosis pathway, and pave the way for mitigating AD.

Cells undergoing ferroptosis in AD exhibit iron overload and oxidative damage, though the precise damage threshold remains unknown. This process may concurrently activate multiple signaling pathways, but synergistic effects between specific pathways require further investigation. Furthermore, certain pathway targets in ferroptosis exhibit bidirectional regulatory effects. Stabilizing the expression of these modulators to exert positive effects in AD represents a critical focus for future research. We must actively develop methods capable of visualizing neuronal ferroptosis in a specific manner during its early stages to clarify the relationship between ferroptosis and AD progression. Assessment of both short-term and long-term impacts of ferroptosis on cellular functions is required. Therefore, there is an urgent need to identify relevant biomarkers that can determine cellular predisposition to ferroptosis and detect ferroptotic events themselves. Iron accumulation and lipid peroxidation may merely represent intermediate events in ferroptosis rather than its terminal executors. Future research must further clarify the ultimate effector molecules of ferroptosis to refine the definition of its complete process. By delving into the unique mechanisms of ferroptosis, we aim to develop novel, safer, and more effective inhibitors for treating AD, ultimately achieving successful clinical translation and application. To optimize the therapeutic potential of ferroptosis inhibitors in protecting AD neurons, careful consideration must be given to patient selection, drug dosage, administration methods, treatment timing, and dosing regimens to maximize benefits while minimizing adverse effects. Furthermore, the safety and pharmacokinetics of certain phytochemicals remain poorly understood, highlighting the necessity for further research to advance their clinical application.

References

[1]       S. J. Dixon et al., ‘Ferroptosis: an iron-dependent form of nonapoptotic cell death’, Cell, vol. 149, no. 5, pp. 1060–1072, May 2012, doi: 10.1016/j.cell.2012.03.042.

[2]       M. Tl, C. Jx, Z. P, Z. Cb, Z. Y, and D. Jx, ‘Focus on ferroptosis regulation: Exploring novel mechanisms and applications of ferroptosis regulator’, Life sciences, vol. 307, Oct. 2022, doi: 10.1016/j.lfs.2022.120868.

[3]       J. X, S. Br, and C. M, ‘Ferroptosis: Mechanisms, biology and role in disease’, Nat. Rev. Mol. Cell Biol., vol. 22, no. 4, Apr. 2021, doi: 10.1038/s41580-020-00324-8.

[4]       S. Sun, J. Shen, J. Jiang, F. Wang, and J. Min, ‘Targeting ferroptosis opens new avenues for the development of novel therapeutics’, Signal Transduction Targeted Ther., vol. 8, no. 1, p. 372, Sep. 2023, doi: 10.1038/s41392-023-01606-1.

[5]       L. Zhang et al., ‘Insight into the double-edged role of ferroptosis in disease’, Biomolecules, vol. 11, no. 12, p. 1790, Nov. 2021, doi: 10.3390/biom11121790.

[6]      D. M. Cammisuli, G. Cipriani, and G. Castelnuovo, ‘Technological solutions for diagnosis, management and treatment of alzheimer’s disease-related symptoms: A structured review of the recent scientific literature’, Int. J. Environ. Res. Public Health, vol. 19, no. 5, p. 3122, Mar. 2022, doi: 10.3390/ijerph19053122.

[7]       P. Scheltens et al., ‘Alzheimer’s disease’, Lancet, vol. 397, no. 10284, pp. 1577–1590, Apr. 2021, doi: 10.1016/S0140-6736(20)32205-4.

[8]      S. Tiwari, V. Atluri, A. Kaushik, A. Yndart, and M. Nair, ‘Alzheimer’s disease: Pathogenesis, diagnostics, and therapeutics’, Int. J. Nanomed., vol. 14, pp. 5541–5554, 2019, doi: 10.2147/IJN.S200490.

[9]       J. Zhang, Y. Zhang, J. Wang, Y. Xia, J. Zhang, and L. Chen, ‘Recent advances in alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies’, Signal Transduction Targeted Ther., vol. 9, no. 1, p. 211, Aug. 2024, doi: 10.1038/s41392-024-01911-3.

[10]     W. J. Streit, L. Phan, and I. Bechmann, ‘Ferroptosis and pathogenesis of neuritic plaques in alzheimer disease’, Pharmacol Rev, vol. 77, no. 1, p. 100005, Jan. 2025, doi: 10.1124/pharmrev.123.000823.

[11]     L. Wu et al., ‘The role of iron metabolism, lipid metabolism, and redox homeostasis in alzheimer’s disease: From the perspective of ferroptosis’, Mol Neurobiol, vol. 60, no. 5, pp. 2832–2850, May 2023, doi: 10.1007/s12035-023-03245-7.

[12]     V. Sharma, P. Sharma, and T. G. Singh, ‘Ferroptosis and alzheimer’s: Unveiling new avenues for the treatment and prevention’, Metab. Brain Dis., vol. 40, no. 4, p. 167, Apr. 2025, doi: 10.1007/s11011-025-01587-w.

[13]     N. Majerníková et al., ‘The link between amyloid β and ferroptosis pathway in alzheimer’s disease progression’, Cell Death Dis, vol. 15, no. 10, p. 782, Oct. 2024, doi: 10.1038/s41419-024-07152-0.

[14]     X. An et al., ‘The effect of tau K677 lactylation on ferritinophagy and ferroptosis in alzheimer’s disease’, Free Radic Biol Med, vol. 224, pp. 685–706, Nov. 2024, doi: 10.1016/j.freeradbiomed.2024.09.021.

[15]     Y. Li et al., ‘Potential therapeutic targets for alzheimer’s disease: Fibroblast growth factors and their regulation of ferroptosis, pyroptosis and autophagy’, Neuroscience, vol. 573, pp. 42–51, May 2025, doi: 10.1016/j.neuroscience.2025.03.009.

[16]     S. Liu, X. Gao, and S. Zhou, ‘New target for prevention and treatment of neuroinflammation: Microglia iron accumulation and ferroptosis’, ASN Neuro, vol. 14, p. 17590914221133236, 2022, doi: 10.1177/17590914221133236.

[17]     M. Wang et al., ‘Revisiting the intersection of microglial activation and neuroinflammation in alzheimer’s disease from the perspective of ferroptosis’, Chem.-Biol. Interact., vol. 375, p. 110387, Apr. 2023, doi: 10.1016/j.cbi.2023.110387.

[18]     E. Mayr et al., ‘Detection of molecular markers of ferroptosis in human alzheimer’s disease brains’, J. Alzheimer’s Dis.: JAD, vol. 102, no. 4, pp. 1133–1154, Dec. 2024, doi: 10.1177/13872877241296563.

[19]     Z. Li, Y. Zhang, M. Ji, C. Wu, Y. Zhang, and S. Ji, ‘Targeting ferroptosis in neuroimmune and neurodegenerative disorders for the development of novel therapeutics’, Biomed. Pharmacother. = Biomed. Pharmacother., vol. 176, p. 116777, Jul. 2024, doi: 10.1016/j.biopha.2024.116777.

[20]     Y. Sun 孙意冉 et al., ‘Inhibition of ferroptosis through regulating neuronal calcium homeostasis: An emerging therapeutic target for alzheimer’s disease’, Ageing Res. Rev., vol. 87, p. 101899, Jun. 2023, doi: 10.1016/j.arr.2023.101899.

[21]     H.-Z. Long, Y. Cheng, Z.-W. Zhou, H.-Y. Luo, D.-D. Wen, and L.-C. Gao, ‘The key roles of organelles and ferroptosis in alzheimer’s disease’, J Neurosci Res, vol. 100, no. 6, pp. 1257–1280, Jun. 2022, doi: 10.1002/jnr.25033.

[22]     X. Zhou et al., ‘Inhibition of VDAC1 rescues aβ 1-42-induced mitochondrial dysfunction and ferroptosis via activation of AMPK and wnt/β-catenin pathways’, Mediators Inflamm, vol. 2023, p. 6739691, 2023, doi: 10.1155/2023/6739691.

[23]     S. Y et al., ‘The inhibition of ORMDL3 prevents alzheimer’s disease through ferroptosis by PERK/ATF4/HSPA5 pathway’, IET Nanobiotechnol., vol. 17, no. 3, May 2023, doi: 10.1049/nbt2.12113.

[24]     Y. Wang et al., ‘Genome-wide mendelian randomization identifies ferroptosis-related drug targets for alzheimer’s disease’, J. Alzheimer’s Dis. Rep., vol. 8, no. 1, pp. 1185–1197, 2024, doi: 10.3233/ADR-240062.

[25]     H. Zhao, J. Wang, Z. Li, S. Wang, G. Yu, and L. Wang, ‘Identification ferroptosis-related hub genes and diagnostic model in alzheimer’s disease’, Front Mol Neurosci, vol. 16, p. 1280639, 2023, doi: 10.3389/fnmol.2023.1280639.

[26]     S. Y, X. Y, T. Q, C. W, and L. L, ‘Genetic markers associated with ferroptosis in alzheimer’s disease’, Front. Aging Neurosci., vol. 16, Apr. 2024, doi: 10.3389/fnagi.2024.1364605.

[27]     C. L et al., ‘Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases’, Signal Transduction Targeted Ther., vol. 10, no. 1, Mar. 2025, doi: 10.1038/s41392-024-02071-0.

[28]     N. Yan and J. Zhang, ‘Iron metabolism, ferroptosis, and the links with alzheimer’s disease’, Front. Neurosci., vol. 13, p. 1443, 2019, doi: 10.3389/fnins.2019.01443.

[29]     Y. Cao et al., ‘Structural changes in cerebral microvasculature induced by ferroptosis contribute to blood-brain barrier disruption in alzheimer’s disease: An autopsy study’, Alzheimer’s Dement.: J. Alzheimer’s Assoc., vol. 21, no. 4, p. e70103, Apr. 2025, doi: 10.1002/alz.70103.

[30]     P. J. Derry et al., ‘Revisiting the intersection of amyloid, pathologically modified tau and iron in alzheimer’s disease from a ferroptosis perspective’, Prog. Neurobiol., vol. 184, p. 101716, Jan. 2020, doi: 10.1016/j.pneurobio.2019.101716.

[31]     F. E et al., ‘Iron overload, microbleeding and the role of bilirubin in alzheimer’s disease brain: Revisiting the vascular hypothesis’, Int. J. Mol. Sci., vol. 26, no. 7, Mar. 2025, doi: 10.3390/ijms26073060.

[32]     P. Lin, J. Wang, Y. Li, G. Li, and Y. Wang, ‘LINC00472 regulates ferroptosis of neurons in alzheimer’s disease via FOXO1’, Dement Geriatr Cogn Disord, vol. 53, no. 3, pp. 107–118, 2024, doi: 10.1159/000537883.

[33]     L. Brase et al., ‘Single-nucleus RNA-sequencing of autosomal dominant alzheimer disease and risk variant carriers’, Nat. Commun., vol. 14, no. 1, p. 2314, Apr. 2023, doi: 10.1038/s41467-023-37437-5.

[34]     A. A. Belaidi et al., ‘Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy’, Mol. Psychiatry, vol. 29, no. 2, pp. 211–220, Feb. 2024, doi: 10.1038/s41380-022-01568-w.

[35]     H. Zhou et al., ‘Integrating bulk and single-cell transcriptomic data to identify ferroptosis-associated inflammatory gene in alzheimer’s disease’, J. Inflammation Res., vol. 18, pp. 2105–2122, 2025, doi: 10.2147/JIR.S497418.

[36]     Y. Zhang, X. Hu, S. Chen, F. Hua, and Z. Zeng, ‘Unveiling the impact of ferroptosis on diabetes-associated cognitive decline through comprehensive single-cell RNA sequencing and experimental studies’, FEBS J., Apr. 2025, doi: 10.1111/febs.70101.

[37]     W. Peng et al., ‘DMT1 knockout abolishes ferroptosis induced mitochondrial dysfunction in C. elegans amyloid β proteotoxicity’, Free Radical Biol. Med., vol. 224, pp. 785–796, Nov. 2024, doi: 10.1016/j.freeradbiomed.2024.09.034.

[38]     W.-D. Bao et al., ‘Loss of ferroportin induces memory impairment by promoting ferroptosis in alzheimer’s disease’, Cell Death Differ., vol. 28, no. 5, pp. 1548–1562, May 2021, doi: 10.1038/s41418-020-00685-9.

[39]     Q. Wang et al., ‘Ferroptosis, pyroptosis, and cuproptosis in alzheimer’s disease’, ACS Chem. Neurosci., vol. 14, no. 19, pp. 3564–3587, Oct. 2023, doi: 10.1021/acschemneuro.3c00343.

[40]     M. Haddad, V. Hervé, M. R. Ben Khedher, J.-M. Rabanel, and C. Ramassamy, ‘Glutathione: An old and small molecule with great functions and new applications in the brain and in alzheimer’s disease’, Antioxid. Redox Signaling, vol. 35, no. 4, pp. 270–292, Aug. 2021, doi: 10.1089/ars.2020.8129.

[41]     J. V. Lana et al., ‘Nebulized glutathione as a key antioxidant for the treatment of oxidative stress in neurodegenerative conditions’, Nutrients, vol. 16, no. 15, p. 2476, Jul. 2024, doi: 10.3390/nu16152476.

[42]     L. Chen et al., ‘Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xFAD mice’, Free Radical Biol. Med., vol. 180, pp. 1–12, Feb. 2022, doi: 10.1016/j.freeradbiomed.2022.01.002.

[43]     Y.-G. Fan et al., ‘Astrocyte-derived lactoferrin inhibits neuronal ferroptosis by reducing iron content and GPX4 degradation in APP/PS1 transgenic mice’, Pharmacol Res, vol. 209, p. 107404, Nov. 2024, doi: 10.1016/j.phrs.2024.107404.

[44]     Y. Maimaiti, T. Su, Z. Zhang, L. Ma, Y. Zhang, and H. Xu, ‘NOX4-mediated astrocyte ferroptosis in alzheimer’s disease’, Cell Biosci., vol. 14, no. 1, p. 88, Jul. 2024, doi: 10.1186/s13578-024-01266-w.

[45]     B. Yan et al., ‘Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1’, Mol. Cell, vol. 81, no. 2, pp. 355-369.e10, Jan. 2021, doi: 10.1016/j.molcel.2020.11.024.

[46]     D. B. Goodenowe and V. Senanayake, ‘Brain ethanolamine phospholipids, neuropathology and cognition: A comparative post-mortem analysis of structurally specific plasmalogen and phosphatidyl species’, Front. Cell Dev. Biol., vol. 10, p. 866156, 2022, doi: 10.3389/fcell.2022.866156.

[47]     L. E. Pope and S. J. Dixon, ‘Regulation of ferroptosis by lipid metabolism’, Trends Cell Biol., vol. 33, no. 12, pp. 1077–1087, Dec. 2023, doi: 10.1016/j.tcb.2023.05.003.

[48]     C. Y.-C. Wu, Y. Zhang, P. Howard, F. Huang, and R. H.-C. Lee, ‘ACSL3 is a promising therapeutic target for alleviating anxiety and depression in alzheimer’s disease’, Geroscience, vol. 47, no. 2, pp. 2383–2397, Apr. 2025, doi: 10.1007/s11357-024-01424-5.

[49]     M. A. Thorwald et al., ‘Iron-associated lipid peroxidation in alzheimer’s disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice’, Alzheimer’s Dement.: J. Alzheimer’s Assoc., vol. 21, no. 1, p. e14541, Jan. 2025, doi: 10.1002/alz.14541.

[50]     P. A. Adeniyi et al., ‘Ferroptosis of microglia in aging human white matter injury’, Ann. Neurol., vol. 94, no. 6, pp. 1048–1066, Dec. 2023, doi: 10.1002/ana.26770.

[51]     J. F. Arboleda-Velasquez et al., ‘Resistance to autosomal dominant alzheimer’s disease in an APOE3 christchurch homozygote: A case report’, Nat. Med., vol. 25, no. 11, pp. 1680–1683, Nov. 2019, doi: 10.1038/s41591-019-0611-3.

[52]     G. G. Sun et al., ‘Microglial APOE3 christchurch protects neurons from tau pathology in a human iPSC-based model of alzheimer’s disease’, Cell Rep, vol. 43, no. 12, p. 114982, Dec. 2024, doi: 10.1016/j.celrep.2024.114982.

[53]     J. Lin et al., ‘Aflatoxin B1 exposure induces alzheimer’s disease like pathology by disrupting redox homeostasis and activating ferroptotic signals in C57BL/6 J mice’, Sci Total Environ, vol. 970, p. 179049, Mar. 2025, doi: 10.1016/j.scitotenv.2025.179049.

[54]     J. Ma et al., ‘Chronic noise exposure induces alzheimer’s disease-like neuropathology and cognitive impairment via ferroptosis in rat hippocampus’, Environ. Health Preventative Med., vol. 29, p. 50, 2024, doi: 10.1265/ehpm.24-00126.

[55]     R. Co et al., ‘Ferroptosis mechanisms involved in neurodegenerative diseases’, Int. J. Mol. Sci., vol. 21, no. 22, p. 8765, Nov. 2020, doi: 10.3390/ijms21228765.

[56]     L. Yang and J. Nao, ‘Ferroptosis: A potential therapeutic target for alzheimer’s disease’, Rev Neurosci, vol. 34, no. 5, pp. 573–598, Jul. 2023, doi: 10.1515/revneuro-2022-0121.

[57]     L. Tao et al., ‘Oleanonic acid ameliorates mutant aβ precursor protein-induced oxidative stress, autophagy deficits, ferroptosis, mitochondrial damage, and ER stress in vitro’, Biochim. Biophys. Acta, Mol. Basis Dis., vol. 1870, no. 8, p. 167459, Dec. 2024, doi: 10.1016/j.bbadis.2024.167459.

[58]     Y. Guo et al., ‘Ghrelin Induces Ferroptosis Resistance and M2 Polarization of Microglia to Alleviate Neuroinflammation and Cognitive Impairment in Alzheimer’s Disease’, J Neuroimmune Pharmacol, vol. 20, no. 1, p. 6, Jan. 2025, doi: 10.1007/s11481-024-10165-3.

[59]     X. Li, X. Wang, B. Huang, and R. Huang, ‘Sennoside A restrains TRAF6 level to modulate ferroptosis, inflammation and cognitive impairment in aging mice with Alzheimer’s Disease’, Int Immunopharmacol, vol. 120, p. 110290, Jul. 2023, doi: 10.1016/j.intimp.2023.110290.

[60]     D. Padhi, P. Baruah, M. Ramesh, H. Moorthy, and T. Govindaraju, ‘Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in alzheimer’s disease’, Redox Biol., vol. 71, p. 103119, May 2024, doi: 10.1016/j.redox.2024.103119.

[61]     X. Chen, C. Yu, R. Kang, G. Kroemer, and D. Tang, ‘Cellular degradation systems in ferroptosis’, Cell Death Differ., vol. 28, no. 4, pp. 1135–1148, Apr. 2021, doi: 10.1038/s41418-020-00728-1.

[62]     C. J. Cardona, Y. Kim, W. Chowanadisai, and M. R. Montgomery, ‘Considerations for using neuroblastoma cell lines to examine the roles of iron and ferroptosis in neurodegeneration’, Cells, vol. 13, no. 18, p. 1541, Sep. 2024, doi: 10.3390/cells13181541.

[63]     V. D’Ezio, M. Colasanti, and T. Persichini, ‘Amyloid-β 25-35 induces neurotoxicity through the up-regulation of astrocytic system xc’, Antioxid. (basel Switz.), vol. 10, no. 11, p. 1685, Oct. 2021, doi: 10.3390/antiox10111685.

[64]     C. Wang et al., ‘Ferroptosis and neurodegenerative diseases: Insights into the regulatory roles of SLC7A11’, Cell. Mol. Neurobiol., vol. 43, no. 6, pp. 2627–2642, Mar. 2023, doi: 10.1007/s10571-023-01343-7.

[65]     L. Wang et al., ‘Research progress on ferroptosis in the pathogenesis and treatment of neurodegenerative diseases’, Front. Cell. Neurosci., vol. 18, p. 1359453, Mar. 2024, doi: 10.3389/fncel.2024.1359453.

[66]     C. Li, K. Cui, X. Zhu, S. Wang, Q. Yang, and G. Fang, ‘8-weeks aerobic exercise ameliorates cognitive deficit and mitigates ferroptosis triggered by iron overload in the prefrontal cortex of APP swe/PSEN 1dE9 mice through xc-/GPx4 pathway’, Front. Neurosci., vol. 18, p. 1453582, 2024, doi: 10.3389/fnins.2024.1453582.

[67]     Z. Hao, X. Guo, J. Wu, and G. Yang, ‘Revisiting the benefits of exercise for alzheimer’s disease through the lens of ferroptosis: A new perspective’, Aging Dis., Dec. 2024, doi: 10.14336/AD.2024.1560.

[68]     L. Cheng et al., ‘Aluminum maltolate triggers ferroptosis in neurons: Mechanism of action’, Toxicol Mech Methods, vol. 31, no. 1, pp. 33–42, Jan. 2021, doi: 10.1080/15376516.2020.1821268.

[69]     J. P. Won, H. J. Yoon, H. G. Lee, and H. G. Seo, ‘Biochanin a inhibits excitotoxicity-triggered ferroptosis in hippocampal neurons’, Eur. J. Pharmacol., vol. 985, p. 177104, Dec. 2024, doi: 10.1016/j.ejphar.2024.177104.

[70]     M. Wang, T. Xuan, H. Li, J. An, T. Hao, and J. Cheng, ‘Protective effect of FXN overexpression on ferroptosis in L-glu-induced SH-SY5Y cells’, Acta Histochem., vol. 126, no. 1, p. 152135, Jan. 2024, doi: 10.1016/j.acthis.2024.152135.

[71]     M. W. Hentze, M. U. Muckenthaler, B. Galy, and C. Camaschella, ‘Two to tango: Regulation of mammalian iron metabolism’, Cell, vol. 142, no. 1, pp. 24–38, Jul. 2010, doi: 10.1016/j.cell.2010.06.028.

[72]     Q. Gao et al., ‘Role of iron in brain development, aging, and neurodegenerative diseases’, Ann. Med., vol. 57, no. 1, p. 2472871, Dec. 2025, doi: 10.1080/07853890.2025.2472871.

[73]     M. Conrad and D. A. Pratt, ‘The chemical basis of ferroptosis’, Nat Chem Biol, vol. 15, no. 12, pp. 1137–1147, Dec. 2019, doi: 10.1038/s41589-019-0408-1.

[74]     T. Liang et al., ‘The critical role of iron homeostasis in neurodegenerative diseases’, Neural Regen Res, Apr. 2025, doi: 10.4103/NRR.NRR-D-24-01382.

[75]     S. Ayton et al., ‘Brain iron is associated with accelerated cognitive decline in people with alzheimer pathology’, Mol. Psychiatry, vol. 25, no. 11, pp. 2932–2941, Nov. 2020, doi: 10.1038/s41380-019-0375-7.

[76]     J. Xu et al., ‘Ferroptosis in alzheimer’s disease: The regulatory role of glial cells’, J. Integr. Neurosci., vol. 24, no. 4, p. 25845, Apr. 2025, doi: 10.31083/JIN25845.

[77]     Y.-J. Liu et al., ‘The role of microglia in neurodegenerative diseases: From the perspective of ferroptosis’, Acta Pharmacol. Sin., pp. 1–16, Apr. 2025, doi: 10.1038/s41401-025-01560-4.

[78]     L.-B. Li et al., ‘Iron exposure and the cellular mechanisms linked to neuron degeneration in adult mice’, Cells, vol. 8, no. 2, p. 198, Feb. 2019, doi: 10.3390/cells8020198.

[79]     F.-X. Liu et al., ‘The role of protein phosphorylation modifications mediated by iron metabolism regulatory networks in the pathogenesis of alzheimer’s disease’, Front. Aging Neurosci., vol. 17, p. 1540019, Feb. 2025, doi: 10.3389/fnagi.2025.1540019.

[80]     D. Guo, Z. Liu, J. Zhou, C. Ke, and D. Li, ‘Significance of programmed cell death pathways in neurodegenerative diseases’, Int. J. Mol. Sci., vol. 25, no. 18, p. 9947, Sep. 2024, doi: 10.3390/ijms25189947.

[81]     M. G. Sabbir, ‘Loss of calcium/calmodulin-dependent protein kinase kinase 2, transferrin, and transferrin receptor proteins in the temporal cortex of alzheimer’s patients postmortem is associated with abnormal iron homeostasis: Implications for patient survival’, Front. Cell Dev. Biol., vol. 12, p. 1469751, 2024, doi: 10.3389/fcell.2024.1469751.

[82]     Y. Xu et al., ‘Astrocyte hepcidin ameliorates neuronal loss through attenuating brain iron deposition and oxidative stress in APP/PS1 mice’, Free Radic Biol Med, vol. 158, pp. 84–95, Oct. 2020, doi: 10.1016/j.freeradbiomed.2020.07.012.

[83]     L. Hao et al., ‘SLC40A1 mediates ferroptosis and cognitive dysfunction in type 1 diabetes’, Neuroscience, vol. 463, pp. 216–226, May 2021, doi: 10.1016/j.neuroscience.2021.03.009.

[84]     J. T. Rogers and C. M. Cahill, ‘Iron-responsive-like elements and neurodegenerative ferroptosis’, Learn. Mem. (cold Spring Harb. N.Y.), vol. 27, no. 9, pp. 395–413, Sep. 2020, doi: 10.1101/lm.052282.120.

[85]     M. A. Khan, ‘Targeting iron responsive elements (IREs) of APP mRNA into novel therapeutics to control the translation of amyloid-β precursor protein in alzheimer’s disease’, Pharm. (basel Switz.), vol. 17, no. 12, p. 1669, Dec. 2024, doi: 10.3390/ph17121669.

[86]     M. C. Cornelis, A. Fazlollahi, D. A. Bennett, J. A. Schneider, and S. Ayton, ‘Genetic markers of postmortem brain iron’, J. Neurochem., vol. 169, no. 2, p. e16309, Feb. 2025, doi: 10.1111/jnc.16309.

[87]     S. Wang, J. Yang, C. Zhen, H. Wang, and P. Shang, ‘Electromagnetic fields regulate iron metabolism: From mechanisms to applications’, J. Adv. Res., pp. S2090-1232(25)288–7, Apr. 2025, doi: 10.1016/j.jare.2025.04.044.

[88]     C. Delaby et al., ‘Plasma hepcidin as a potential informative biomarker of alzheimer disease and vascular dementia’, Alzheimers Res Ther, vol. 17, no. 1, p. 42, Feb. 2025, doi: 10.1186/s13195-025-01696-9.

[89]     B. B. Muhoberac and R. Vidal, ‘Iron, ferritin, hereditary ferritinopathy, and neurodegeneration’, Front. Neurosci., vol. 13, p. 1195, 2019, doi: 10.3389/fnins.2019.01195.

[90]     C. Z et al., ‘Decursin ameliorates neurotoxicity induced by glutamate through restraining ferroptosis by up-regulating FTH1 in SH-SY5Y neuroblastoma cells’, Neuroscience, vol. 559, Jan. 2024, doi: 10.1016/j.neuroscience.2024.08.035.

[91]     B. Wang et al., ‘ROS-induced lipid peroxidation modulates cell death outcome: Mechanisms behind apoptosis, autophagy, and ferroptosis’, Arch. Toxicol., vol. 97, no. 6, pp. 1439–1451, Jun. 2023, doi: 10.1007/s00204-023-03476-6.

[92]     I. Costa et al., ‘Molecular mechanisms of ferroptosis and their involvement in brain diseases’, Pharmacology & Therapeutics, vol. 244, p. 108373, Apr. 2023, doi: 10.1016/j.pharmthera.2023.108373.

[93]     D. Liang, A. M. Minikes, and X. Jiang, ‘Ferroptosis at the intersection of lipid metabolism and cellular signaling’, Mol Cell, vol. 82, no. 12, pp. 2215–2227, Jun. 2022, doi: 10.1016/j.molcel.2022.03.022.

[94]     A. Currais, D. Kepchia, Z. Liang, and P. Maher, ‘The role of AMP-activated protein kinase in oxytosis/ferroptosis: Protector or potentiator?’, Antioxid Redox Signal, vol. 41, no. 16–18, pp. e1173–e1186, Dec. 2024, doi: 10.1089/ars.2022.0013.

[95]     D.-L. He, Y.-G. Fan, and Z.-Y. Wang, ‘Energy crisis links to autophagy and ferroptosis in alzheimer’s disease: Current evidence and future avenues’, Curr. Neuropharmacol., vol. 21, no. 1, pp. 67–86, 2023, doi: 10.2174/1570159X20666220817140737.

[96]     B. Tong et al., ‘Targeting dysregulated lipid metabolism for the treatment of Alzheimer’s disease and Parkinson’s disease: Current advancements and future prospects’, Neurobiol. Dis., vol. 196, p. 106505, Jun. 2024, doi: 10.1016/j.nbd.2024.106505.

[97]     Y. Li et al., ‘7-dehydrocholesterol dictates ferroptosis sensitivity’, Nature, vol. 626, no. 7998, pp. 411–418, Feb. 2024, doi: 10.1038/s41586-023-06983-9.

[98]     X. Zha et al., ‘Microbiota-derived lysophosphatidylcholine alleviates alzheimer’s disease pathology via suppressing ferroptosis’, Cell Metab., vol. 37, no. 1, pp. 169-186.e9, Jan. 2025, doi: 10.1016/j.cmet.2024.10.006.

[99]     J. H. Yang, C. D. Nguyen, G. Lee, and C.-S. Na, ‘Insamgobonhwan protects neuronal cells from lipid ROS and improves deficient cognitive function’, Antioxidants (Basel), vol. 11, no. 2, p. 295, Jan. 2022, doi: 10.3390/antiox11020295.

[100]   Z.-Y. Zhu et al., ‘Mitochondrial aldehyde dehydrogenase (ALDH2) rescues cardiac contractile dysfunction in an APP/PS1 murine model of alzheimer’s disease via inhibition of ACSL4-dependent ferroptosis’, Acta Pharmacol. Sin., vol. 43, no. 1, pp. 39–49, Jan. 2022, doi: 10.1038/s41401-021-00635-2.

[101]   S. Doll et al., ‘FSP1 is a glutathione-independent ferroptosis suppressor’, Nature, vol. 575, no. 7784, pp. 693–698, Nov. 2019, doi: 10.1038/s41586-019-1707-0.

[102]   K. Bersuker et al., ‘The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis’, Nature, vol. 575, no. 7784, pp. 688–692, Nov. 2019, doi: 10.1038/s41586-019-1705-2.

[103]   Z. Fišar and J. Hroudová, ‘CoQ10 and mitochondrial dysfunction in alzheimer’s disease’, Antioxid. (basel Switz.), vol. 13, no. 2, p. 191, Feb. 2024, doi: 10.3390/antiox13020191.

[104]   J.-S. Yang et al., ‘ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1’, Cell, pp. S0092-8674(25)292–2, Apr. 2025, doi: 10.1016/j.cell.2025.03.019.

[105]   J. Kim and J.-S. Moon, ‘Molecular roles of NADPH oxidase-mediated oxidative stress in alzheimer’s disease: Isoform-specific contributions’, Int. J. Mol. Sci., vol. 25, no. 22, p. 12299, Nov. 2024, doi: 10.3390/ijms252212299.

[106]   H. Tan et al., ‘Dual targeting of FSP1 and xCT: Potential mechanism of anthocyanins in alleviating neuronal ferroptosis in vascular dementia’, Phytomed.: Int. J. Phytother. Phytopharm., vol. 142, p. 156608, Mar. 2025, doi: 10.1016/j.phymed.2025.156608.

[107]   M. Sun et al., ‘Insulin attenuates LPS-induced cognitive impairment and ferroptosis through regulation of glucose metabolism in hippocampus’, CNS Neurosci Ther, vol. 30, no. 7, p. e14887, Jul. 2024, doi: 10.1111/cns.14887.

[108]   F. J. Jiménez-Jiménez, H. Alonso-Navarro, E. García-Martín, and J. A. G. Agúndez, ‘Coenzyme Q10 and dementia: A systematic review’, Antioxidants (Basel), vol. 12, no. 2, p. 533, Feb. 2023, doi: 10.3390/antiox12020533.

[109]   S. M. Ahmadi-Soleimani, S. Ghasemi, M. A. Rahmani, M. Gharaei, M. Mohammadi Bezanaj, and F. Beheshti, ‘Oral administration of coenzyme Q10 ameliorates memory impairment induced by nicotine-ethanol abstinence through restoration of biochemical changes in Male rat hippocampal tissues’, Sci Rep, vol. 14, no. 1, p. 11413, May 2024, doi: 10.1038/s41598-024-61932-4.

[110]   C. J, S. Z, C. Y, X. K, W. Y, and Z. H, ‘A CoQ10 analog ameliorates cognitive impairment and early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation’, Redox Biol., vol. 84, May 2025, doi: 10.1016/j.redox.2025.103684.

[111]   X. Yang and C. Tohda, ‘Diosgenin restores memory function via SPARC-driven axonal growth from the hippocampus to the PFC in alzheimer’s disease model mice’, Mol. Psychiatry, vol. 28, no. 6, pp. 2398–2411, Jun. 2023, doi: 10.1038/s41380-023-02052-9.

[112]   L. Wang et al., ‘Diosgenin alleviates lipid accumulation in NAFLD through the pathways of ferroptosis defensive and executive system’, J. Nutr. Biochem., vol. 140, p. 109886, Jun. 2025, doi: 10.1016/j.jnutbio.2025.109886.

[113]   P. Gupta and R. Kumar, ‘GTP cyclohydroxylase1 (GCH1): Role in neurodegenerative diseases’, Gene, vol. 888, p. 147749, Dec. 2023, doi: 10.1016/j.gene.2023.147749.

[114]   X. Wei, X. Yi, X.-H. Zhu, and D.-S. Jiang, ‘Posttranslational modifications in ferroptosis’, Oxid. Med. Cell. Longevity, vol. 2020, p. 8832043, Nov. 2020, doi: 10.1155/2020/8832043.

[115]   Q. Hu et al., ‘Blockade of GCH1/BH4 axis activates ferritinophagy to mitigate the resistance of colorectal cancer to erastin-induced ferroptosis’, Front Cell Dev Biol, vol. 10, p. 810327, Feb. 2022, doi: 10.3389/fcell.2022.810327.

[116]   V. A. N. Kraft et al., ‘GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling’, ACS Cent Sci, vol. 6, no. 1, pp. 41–53, Jan. 2020, doi: 10.1021/acscentsci.9b01063.

[117]   H. Fanet, L. Capuron, N. Castanon, F. Calon, and S. Vancassel, ‘Tetrahydrobioterin (BH4) pathway: From metabolism to neuropsychiatry’, Curr Neuropharmacol, vol. 19, no. 5, pp. 591–609, 2021, doi: 10.2174/1570159X18666200729103529.

[118]   ‘Recommendations for robust and reproducible research on ferroptosis – PubMed’. Accessed: Jun. 13, 2025. [Online]. Available: https://pubmed.ncbi.nlm.nih.gov/40204928/

[119]   X. Zhou et al., ‘Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis’, Proc. Natl. Acad. Sci. U. S. A., vol. 115, no. 8, pp. 1697–1706, Feb. 2018, doi: 10.1073/pnas.1715554115.

[120]   C.-L. Gan, T. Zhang, and T. H. Lee, ‘The genetics of alzheimer’s disease in the Chinese population’, Int. J. Mol. Sci., vol. 21, no. 7, p. 2381, Mar. 2020, doi: 10.3390/ijms21072381.

[121]   M. Ma, D. Xie, and J. Zhao, ‘Bioinformatics and experimental identification of circ_0001535 associated with diagnosis and development of alzheimer’s disease’, J. Integr. Neurosci., vol. 22, no. 4, p. 105, Jul. 2023, doi: 10.31083/j.jin2204105.

[122]   H. Fanet et al., ‘Tetrahydrobiopterin improves recognition memory in the triple-transgenic mouse model of alzheimer’s disease, without altering amyloid-β and tau pathologies’, J Alzheimers Dis, vol. 79, no. 2, pp. 709–727, 2021, doi: 10.3233/JAD-200637.

[123]   J. Du et al., ‘CTRP13 attenuates atherosclerosis by inhibiting endothelial cell ferroptosis via activating GCH1’, Int. Immunopharmacol., vol. 143, no. Pt 3, p. 113617, Dec. 2024, doi: 10.1016/j.intimp.2024.113617.

[124]   Z. Liu et al., ‘Endothelial cell-derived tetrahydrobiopterin prevents aortic valve calcification’, Eur Heart J, vol. 43, no. 17, pp. 1652–1664, May 2022, doi: 10.1093/eurheartj/ehac037.

[125]   W. Y et al., ‘Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases’, Signal Transduction Targeted Ther., vol. 8, no. 1, p. 449, Oct. 2023, doi: 10.1038/s41392-023-01720-0.

[126]   M. Mohan, A. Mannan, C. Kakkar, and T. G. Singh, ‘Nrf2 and ferroptosis: Exploring translational avenues for therapeutic approaches to neurological diseases’, Curr. Drug Targets, Sep. 2024, doi: 10.2174/0113894501320839240918110656.

[127]   K. Itoh, J. Mimura, and M. Yamamoto, ‘Discovery of the negative regulator of Nrf2, Keap1: A historical overview’, Antioxid Redox Signal, vol. 13, no. 11, pp. 1665–1678, Dec. 2010, doi: 10.1089/ars.2010.3222.

[128]   D. J. R. Lane, B. Metselaar, M. Greenough, A. I. Bush, and S. J. Ayton, ‘Ferroptosis and NRF2: an emerging battlefield in the neurodegeneration of Alzheimer’s disease’, Essays Biochem, vol. 65, no. 7, pp. 925–940, Dec. 2021, doi: 10.1042/EBC20210017.

[129]   M. Pajares, A. Cuadrado, and A. I. Rojo, ‘Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases’, Redox Biol., vol. 11, pp. 543–553, Jan. 2017, doi: 10.1016/j.redox.2017.01.006.

[130]   L. L, J. C, X. J, and W. J, ‘E3 ligases and DUBs target ferroptosis: A potential therapeutic strategy for neurodegenerative diseases’, Biomed. Pharmacother. = Biomed. Pharmacother., vol. 175, Jun. 2024, doi: 10.1016/j.biopha.2024.116753.

[131]   C. Jo, S. Gundemir, S. Pritchard, Y. N. Jin, I. Rahman, and G. V. W. Johnson, ‘Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52’, Nat Commun, vol. 5, p. 3496, Mar. 2014, doi: 10.1038/ncomms4496.

[132]   C. Luo et al., ‘Role of miRNA regulation in IGFBP-2 overexpression and neuronal ferroptosis: Insights into the Nrf2/SLC7A11/GPX4 pathway in alzheimer’s disease’, Int. J. Biol. Macromol., vol. 287, p. 138537, Jan. 2025, doi: 10.1016/j.ijbiomac.2024.138537.

[133]   G. Bahn et al., ‘NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models’, Proc Natl Acad Sci U S A, vol. 116, no. 25, pp. 12516–12523, Jun. 2019, doi: 10.1073/pnas.1819541116.

[134]   Z. Mu, Z. Sun, S. Wu, J. Yang, P. Wang, and X. Zhao, ‘Trehalose inhibits ferroptosis through activating SIRT3/SOD2 signaling axis and alleviates brain injury after traumatic brain injury’, Neurochem Res, vol. 50, no. 1, p. 78, Jan. 2025, doi: 10.1007/s11064-024-04330-6.

[135]   P. Soni, S. M. Sharma, A. A. Pieper, B. D. Paul, and B. Thomas, ‘Nrf2/Bach1 signaling axis: A promising multifaceted therapeutic strategy for alzheimer’s disease’, Neurother.: J. Am. Soc. Exp. Neurother., vol. 22, no. 3, p. e00586, Apr. 2025, doi: 10.1016/j.neurot.2025.e00586.

[136]   L. Casares et al., ‘Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity’, Redox Biol., vol. 37, p. 101689, Oct. 2020, doi: 10.1016/j.redox.2020.101689.

[137]   E. Cazalla, A. Cuadrado, and Á. J. García-Yagüe, ‘Role of the transcription factor NRF2 in maintaining the integrity of the blood-brain barrier’, Fluids Barriers CNS, vol. 21, p. 93, Nov. 2024, doi: 10.1186/s12987-024-00599-5.

[138]   R. Ni, J. Jiang, F. Wang, and J. Min, ‘Treating incurable non-communicable diseases by targeting iron metabolism and ferroptosis’, Sci. China, Life Sci., Feb. 2025, doi: 10.1007/s11427-024-2787-y.

[139]   M. Alrouji et al., ‘Iron homeostasis and neurodegeneration in the ageing brain: Insight into ferroptosis pathways’, Ageing Res. Rev., vol. 102, p. 102575, Dec. 2024, doi: 10.1016/j.arr.2024.102575.

[140]   C. Sun et al., ‘Berberine alleviates alzheimer’s disease by activating autophagy and inhibiting ferroptosis through the JNK-p38MAPK signaling pathway’, Int. Immunopharmacol., vol. 155, p. 114550, May 2025, doi: 10.1016/j.intimp.2025.114550.

[141]   X. Li et al., ‘Berberine ameliorates iron levels and ferroptosis in the brain of 3 × tg-AD mice’, Phytomed.: Int. J. Phytother. Phytopharm., vol. 118, p. 154962, Sep. 2023, doi: 10.1016/j.phymed.2023.154962.

[142]   Q. Lu et al., ‘The anti-alzheimer’s disease effects of ganoderic acid a by inhibiting ferroptosis-lipid peroxidation via activation of the NRF2/SLC7A11/GPX4 signaling pathway’, Chem.-Biol. Interact., vol. 412, p. 111459, May 2025, doi: 10.1016/j.cbi.2025.111459.

[143]   M. Wang et al., ‘Saponins from astragalus membranaceus (fisch.) bge alleviated neuronal ferroptosis in alzheimer’s disease by regulating the NOX4/Nrf2 signaling pathway’, J. Agric. Food Chem., vol. 73, no. 13, pp. 7725–7740, Apr. 2025, doi: 10.1021/acs.jafc.4c10497.

[144]   X. Meng et al., ‘Lignans from schisandra chinensis (turcz.) baill ameliorates cognitive impairment in alzheimer’s disease and alleviates ferroptosis by activating the Nrf2/FPN1 signaling pathway and regulating iron levels’, J Ethnopharmacol, vol. 341, p. 119335, Feb. 2025, doi: 10.1016/j.jep.2025.119335.

[145]   Y. Feng et al., ‘Hederagenin ameliorates ferroptosis-induced damage by regulating PPARα/Nrf2/GPX4 signaling pathway in HT22 cells: An in vitro and in silico study’, Bioorg. Chem., vol. 155, p. 108119, Feb. 2025, doi: 10.1016/j.bioorg.2024.108119.

[146]   T. L et al., ‘Proteomic alteration in catalpol treatment of alzheimer’s disease by regulating HSPA5/ GPX4’, Eur. J. Pharmacol., vol. 987, p. 177075, Jan. 2025, doi: 10.1016/j.ejphar.2024.177075.

[147]   Z. Li et al., ‘Avicularin inhibits ferroptosis and improves cognitive impairments in alzheimer’s disease by modulating the NOX4/Nrf2 axis’, Phytomed.: Int. J. Phytother. Phytopharm., vol. 135, p. 156209, Dec. 2024, doi: 10.1016/j.phymed.2024.156209.

[148]   Y. Yong et al., ‘A novel ferroptosis inhibitor, thonningianin a, improves alzheimer’s disease by activating GPX4’, Theranostics, vol. 14, no. 16, pp. 6161–6184, 2024, doi: 10.7150/thno.98172.

[149]   S. Yang et al., ‘Salidroside alleviates cognitive impairment by inhibiting ferroptosis via activation of the Nrf2/GPX4 axis in SAMP8 mice’, Phytomedicine, vol. 114, p. 154762, Jun. 2023, doi: 10.1016/j.phymed.2023.154762.

[150]   S. Yang et al., ‘Salidroside attenuates neuronal ferroptosis by activating the Nrf2/HO1 signaling pathway in Aβ1-42-induced alzheimer’s disease mice and glutamate-injured HT22 cells’, Chin. Med., vol. 17, no. 1, p. 82, Jul. 2022, doi: 10.1186/s13020-022-00634-3.

[151]   L. Li et al., ‘Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation’, Mol. Med., vol. 28, no. 1, p. 11, Jan. 2022, doi: 10.1186/s10020-022-00442-3.

[152]   Y. Wu et al., ‘Schisandra total lignans ameliorate neuronal ferroptosis in 3xTg-AD mice via regulating NADK/NADPH/GSH pathway’, Phytomed.: Int. J. Phytother. Phytopharm., vol. 140, p. 156612, May 2025, doi: 10.1016/j.phymed.2025.156612.

[153]   Y. Gao et al., ‘Tetrahydroxy stilbene glycoside ameliorates alzheimer’s disease in APP/PS1 mice via glutathione peroxidase related ferroptosis’, Int Immunopharmacol, vol. 99, p. 108002, Oct. 2021, doi: 10.1016/j.intimp.2021.108002.

[154]   N. Xia et al., ‘Neuroprotective effect of emodin on Aβ25-35-induced cytotoxicity in PC12 cells involves Nrf2/GPX4 and TLR4/p-NF-κB/NLRP3 pathways’, Brain Res., vol. 1841, p. 149019, Oct. 2024, doi: 10.1016/j.brainres.2024.149019.

[155]   P.-X. Deng et al., ‘Artemisinin inhibits neuronal ferroptosis in alzheimer’s disease models by targeting KEAP1’, Acta Pharmacol. Sin., vol. 46, no. 2, pp. 326–337, Feb. 2025, doi: 10.1038/s41401-024-01378-6.

[156]   C. Song et al., ‘Water extract of moschus alleviates erastin-induced ferroptosis by regulating the Keap1/Nrf2 pathway in HT22 cells’, J Ethnopharmacol, vol. 326, p. 117937, Feb. 2024, doi: 10.1016/j.jep.2024.117937.

[157]   T. Ding, M. Song, Y. Wu, Z. Li, S. Zhang, and X. Fan, ‘Schisandrin B ameliorates alzheimer’s disease by suppressing neuronal ferroptosis and ensuing microglia M1 polarization’, Phytomed.: Int. J. Phytother. Phytopharm., vol. 142, p. 156780, Jul. 2025, doi: 10.1016/j.phymed.2025.156780.

[158]   Y. Gong, Y. Wang, Y. Li, F. Weng, T. Chen, and L. He, ‘Curculigoside, a traditional Chinese medicine monomer, ameliorates oxidative stress in alzheimer’s disease mouse model via suppressing ferroptosis’, Phytotherapy research: PTR, vol. 38, no. 5, pp. 2462–2481, May 2024, doi: 10.1002/ptr.8152.

[159]   L. Shao, C. Dong, D. Geng, Q. He, and Y. Shi, ‘Ginkgolide B protects against cognitive impairment in senescence-accelerated P8 mice by mitigating oxidative stress, inflammation and ferroptosis’, Biochem Biophys Res Commun, vol. 572, pp. 7–14, Oct. 2021, doi: 10.1016/j.bbrc.2021.07.081.

[160]   D. Song et al., ‘Neuritin improves cognitive impairments in APP/PS1 alzheimer’s disease mice model by mitigating neuronal ferroptosis via PI3K/akt activation’, Int. J. Biol. Macromol., vol. 303, p. 140662, Apr. 2025, doi: 10.1016/j.ijbiomac.2025.140662.

[161]   X. Ren et al., ‘Cerebroprotein hydrolysate-I ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via the p53/SAT1/ALOX15 signalling pathway’, Eur J Pharmacol, vol. 979, p. 176820, Sep. 2024, doi: 10.1016/j.ejphar.2024.176820.

[162]   L. Qiao, G. Li, and H.-X. Yuan, ‘Dexmedetomidine mediates the mechanism of action of ferroptosis in mice with alzheimer’s disease by regulating the mTOR-TFR1 pathway’, World J. Psychiatry, vol. 13, no. 8, pp. 511–523, Aug. 2023, doi: 10.5498/wjp.v13.i8.511.