Aβ plaque accumulation is a hallmark pathological feature of AD, where abnormal Aβ aggregation disrupts synaptic function and impairs memory (30,31). Aβ, composed of 39–43 amino acids, is cleaved from amyloid precursor protein (APP) (32). APP is a highly conserved protein involved in synapse formation, dendritic growth and neuronal migration (33). Iron facilitates the dissociation of iron regulatory protein (IRP) 1 from the iron-responsive element (IRE) (34). Elevated intracellular iron levels disrupt the IRP/IRE signaling pathway, leading to increased expression of APP (35,36) and Aβ production. Additionally, Fe²⁺ binds to the N-terminal domain of Aβ, destabilizing its helical structure and promoting peptide aggregation by enhancing peptide-peptide interactions (37). Concurrently, τ hyperphosphorylation and its abnormal accumulation, coupled with impaired clearance, lead to the formation of NFTs, further compromising neuronal function. NFT formation is a key pathological hallmark of AD (38–41). Dysregulated iron homeostasis has been linked to τ hyperphosphorylation and NFT development (42). In the cortex and hippocampus of patients with AD, NFTs accumulate in response to increased iron levels (43). Excessive neuronal iron promotes NFT formation via the activation of CDK5 (Cyclin-dependent kinase 5)/P25 complexes and GSK-3β (Glycogen synthase kinase-3 beta) kinase pathways. Fe³⁺ also induces hyperphosphorylated τ aggregation by binding to the histidine residues of τ (44–46).

Microglia are essential components of the central nervous system (CNS), serving key roles in energy metabolism, synaptic plasticity and ion homeostasis. In addition, microglia serve as resident immune cells, engaging in immune responses with memory-like behavior and maintaining brain homeostasis. During neurodegenerative processes, microglial activation is frequently observed, with increasing evidence suggesting that iron overload and disrupted iron homeostasis contribute to neurodegeneration in AD (47,48). As such, microglia serve a key role in neurological disorder. In response to infection or tissue injury, microglia rapidly adapt to the local environment, undergoing activation that can result in either beneficial or harmful outcomes. Kroner et al (49) demonstrated that elevated iron levels in microglia promote phagocytosis and drive a harmful M1 phenotype, which triggers the release of pro-inflammatory factors such as TNF-α, IL-1β, IL-6 and nitric oxide (NO), causing neuronal damage. Similarly, Rao et al (50) found that increased intracellular iron disrupts the neuromelanin-iron complex in neurons, releasing free iron ions that damage neurons and lead to neuromelanin leakage. This leakage further activates microglia towards the M1 phenotype, promoting release of neurotoxic agents, including TNF-α and IL-6 (50). Moreover, iron accumulation in activated microglia contributes to iron deposition within the CNS (51,52). In the M1 state, microglia express inducible NO synthase (iNOS), which converts arginine into NO. The resulting NO accumulation exacerbates glutamate-induced neurotoxicity, contributing to neuronal ferroptosis (53).

Ferroptosis, an iron-dependent form of cell death distinct from apoptosis and necrosis, is primarily triggered by oxidative stress, a key pathological process in AD. The accumulation of reactive oxygen species (ROS), a hallmark of oxidative stress, serves a key role in initiating ferroptosis. Oxidative stress affects numerous molecular pathways, including inhibition of the cystine/glutamate antiporter system, decreased expression of GPX4, disruption of iron homeostasis and lipid peroxidation, which is a major driver of ferroptosis activation (54). Excess lipid peroxide accumulation in cells, a key feature of ferroptosis, results from a free radical chain reaction. Oxygen radicals insert into the C-H bonds of PUFAs, generating lipid hydroperoxides and elevating levels of ROS, which induce ferroptosis (55). Malondialdehyde, a byproduct of lipid peroxidation, is a marker for both ferroptosis and oxidative stress (56). Furthermore, oxidative stress impairs the antioxidant defense system by decreasing expression of key enzymes such as GSH, catalase, superoxide dismutase and GPX, thus accelerating ferroptosis (56,57). Neuronal loss, a defining characteristic of neurodegenerative disease, is associated with cognitive decline in AD (58). Elevated iron levels promote ROS production, depleting intracellular GSH levels and accelerating lipid peroxidation. This cascade leads to ferroptosis, contributing to neuronal death (59). Bao et al (60) found downregulation of the ferroptosis regulator GPX4 in both Fpn^fl/fl/NEXcre (NEX-Cre mice were mated with Fpn-floxed (Fpnfl/fl) mice to generate conditional Fpn^fl/fl/NEXcre mice.) and APPswe/PS1dE9 (Carrying genetically modified mice with AD-related mutations: a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9) mouse models compared with controls. Additionally, mRNA expression of iron response element binding protein 2, encodes a master regulator of iron metabolism), and CS (citrate synthase, regulating the mitochondrial fatty acid metabolism) was upregulated in both models, while ACSF2 ((acyl-CoA synthetase family member 2, regulating the mitochondrial fatty acid metabolism) was upregulated only in APPswe/PS1dE9 mice. These findings suggest that ferroptosis is activated in the hippocampus of both mouse models.

In cellular defense against oxidative stress, the Keap1/Nrf2/ARE signaling pathway regulates the expression of various proteins involved in detoxification and antioxidant defense, positioning it as a potential target for AD treatment (61). Nrf2, a transcription factor that is highly responsive to oxidative stress, serves a key role in mitigating lipid peroxidation and ferroptosis (62). Under physiological conditions, Keap1 suppresses Nrf2 by facilitating its ubiquitination and degradation via the ubiquitin-proteasome system. By contrast, during oxidative stress, Nrf2 dissociates from Keap1, translocates to the nucleus, forms a heterodimer with small musculoaponeurotic fibrosarcoma oncogene homolog proteins and binds to ARE, thereby enhancing the transcription of antioxidant genes (63–65). Nrf2 regulates key components of anti-ferroptotic pathways, positioning it as a central modulator of lipid peroxidation and ferroptosis (62). In the nucleus, Nrf2 induces the expression of cytoprotective genes that mitigate ferroptosis by regulating iron metabolism and enhancing antioxidant defenses. This includes the upregulation of ferritin heavy and light chain, ferroportin, transferrin receptor and heme oxygenase-1 (HO-1), alongside increased production of NADPH, GSH and CoQ10 (coenzyme Q10) which counter lipid peroxidation and suppress ferroptosis (66,67). Moreover, the detachment of the DLG motif of Nrf2 from Keap1 prevents its ubiquitination and degradation, thus strengthening antioxidant defenses and inhibiting ferroptosis (68).

This process is initiated when unsaturated FAs in cell membranes undergo catalytic lipid peroxidation, driven by divalent iron or esteroxygenases, leading to cell death (69–71). The p53 protein, a key human tumor suppressor, regulates the expression of oncogenes and downstream signaling pathways, contributing to biological effects (72–75): Beyond its role in cancer, p53 is highly expressed in the brain, where it influences dendritic growth, oxidative stress response, apoptosis and autophagy, making p53 dysfunction and associated pathways noteworthy in the pathogenesis of AD (76–78). SLC7A11, a key ferroptosis regulator, is a transmembrane protein that is part of the system Xc⁻, responsible for cystine import into cells for cysteine synthesis and GSH production (79,80). Downregulation of SLC7A11 disrupts cysteine metabolism, leading to decreased intracellular cystine and GSH levels, impairing GPX4 activity and triggering lipid peroxide accumulation and ferroptosis (79,81,82). Studies indicate that p53 binds the SLC7A11 promoter, suppressing its expression and limiting GSH production, thereby promoting ferroptosis (83,84). Aristolochic acid, mediated by p53, may limit ferroptosis in liver cancer to enhance tumor growth. The p53(3KR) mutant, lacking acetylation due to lysine-to-arginine substitutions at three residues, decreases expression of SLC7A11 without affecting other p53 targets such as CDKN1A/p21 (involved in cell cycle progression) or BAX (involved in apoptosis). By contrast, the p53(4KR98) mutant, with an additional lysine 98 substitution, does not downregulate SLC7A11 (85–87).

In AD, excessive lipid peroxide accumulation is a key initiator of ferroptosis, with elevated markers of lipid peroxidation observed in neurons. Iron accumulation drives the Fenton and Haber-Weiss reactions, generating ROS that induce lipid peroxidation, leading to oxidative damage to subcellular structures (88). GPX4 and GSH are key regulators of ferroptosis. GSH, containing a thiol group derived from cysteine, serves as a vital antioxidant, neutralizing ROS and reactive nitrogen species, maintaining cellular redox balance and detoxifying xenobiotics (89). GPX4, a selenium (Se)-dependent enzyme, relies on a Se-containing amino acid residue to execute its reductive function (90). It converts lipid hydroperoxides into less harmful lipid alcohols, preventing oxidative damage (91,92). The active site of GPX4, selenocysteine, alternates between reduced and oxidized states to sustain its catalytic activity. In the presence of peroxides, the selenolate form of GPX4 is oxidized to selenic acid, which is regenerated to its active form by two molecules of reduced GSH, converting lipid hydroperoxides into non-toxic lipid alcohols and generating oxidized GSH (16,92–94). This highlights the key role of GPX4 synthesis and its associated pathways in the regulation of ferroptosis.

Vitamin E, an antioxidant in AD treatment, inhibits ferroptosis primarily by preventing lipid peroxidation (101). It consists of two subclasses: Tocotrienols and tocopherols, with four saturated analogs (α, β, γ and δ) (132,133). These lipophilic compounds, along with their derivatives, serve as radical-trapping antioxidants, preventing the formation of phospholipid hydroperoxides. As the dominant form in tissue, α-tocopherol exerts its antioxidant effects by interrupting the chain reaction of lipid oxidation. Specifically, the oxidative conversion of α-tocopherol produces α-tocopherol quinone, which is reduced to α-tocopherol hydroquinone. This reduction is key for inhibiting the enzymatic activity of 15-lipoxygenase, primarily by converting its non-heme Fe³⁺ to an inactive Fe²⁺ state. This inhibition disrupts the ferroptotic signaling cascade, effectively preventing lipid peroxidation and mitigating ferroptosis (106). α-tocopherol transfer protein (TTP), which is abundant in the brain, regulates α-tocopherol levels and distribution (107). Vitamin E or TTP deficiency induce oxidative stress in the brain. Studies show that patients with AD exhibit reduced vitamin E levels in plasma, serum and cerebrospinal fluid, and those receiving vitamin E supplementation experience slower cognitive decline and decreased oxidative stress compared with placebo-treated individuals (101,108). These findings suggest that vitamin E deficiency contributes to neurodegeneration, while supplementation may offer protection against ferroptotic stress.

Se, an essential trace element involved in GPX4 synthesis, is incorporated into several proteins in the body (109). Known for its antioxidant properties, Se also serves a role in inhibiting ferroptosis (102,110). Clinical studies suggest Se may have potential in mitigating cognitive decline (111,134). In a mouse model of stroke, intracerebroventricular sodium selenate treatment elevates GPX4 levels by activating transcription factors activating enhancer binding protein 2γ and specificity protein 1, while also providing protection against excitotoxicity and endoplasmic reticulum stress-induced cell death independent of GPX4 (102). Decreased Se levels in the brains of patients with AD are associated with disease progression. In primary neuronal cultures, Se was shown to decrease Aβ production by downregulating 4-hydroxy-2-nonenal-induced β-secretase transcription, thus preventing Aβ-associated toxicity (102). Se-containing compounds inhibit ferroptosis by upregulating GPX4. A clinical trial demonstrated that oral sodium selenate supplementation increases brain Se levels without notable side effects, and participants with improved Se levels do not exhibit worsening Mini-Mental State Examination scores over time (108). However, Kryscio et al (108) revealed that both Se and vitamin E have adverse effects on progression of AD in male patients. Thus, current evidence does not definitively support a potential therapeutic role of Se in AD, and further clinical trials are needed to clarify its effects.

Fer-1, the first synthetic ferroptosis inhibitor, has served as a pivotal reference compound (27). It effectively prevents oxidative lipid damage and cell death in disease models, including Huntington's disease, periventricular leukomalacia, renal dysfunction, cerebral hemorrhage and cardiomyopathy (103,112,113). As a highly specific ferroptosis inhibitor, Fer-1 surpasses phenolic antioxidants in its ability to suppress ferroptosis, particularly by inhibiting lipid ROS accumulation induced by erastin or RSL3 in HT-1080 human fibrosarcoma cells) (27). The anti-ferroptotic action of Fer-1 primarily arises from its capacity to scavenge alkoxyl radicals and reactive species generated by ferrous iron in lipid hydroperoxides. Additionally, it reduces labile iron, as confirmed by calcein fluorescence assays, further supporting its iron-complexing properties (114). In HT-22 (mouse hippocampal neurons cells) cells, Fer-1 notably decreases both cytoplasmic and lipid ROS levels, counteracts glutamate-induced suppression of GSH and GPX activity and protects against oxidative toxicity. Furthermore, Fer-1 mitigates oxidative stress by downregulating prostaglandin endoperoxide synthase 2 while upregulating GPX4 and Nrf2, thereby decreasing lipid peroxidation (115). Despite its documented efficacy in vitro and in vivo in alleviating oxidative stress and preventing iron deficiency, Fer-1 remains untested in clinical trials (114). Further investigation is required to assess its therapeutic potential, safety and clinical effectiveness for treating AD.

NAC, a cysteine precursor, is used to treat acetaminophen overdose and is listed as an essential medicine by the World Health Organization (116). In addition to its role in treating acute poisoning, NAC is recognized for its pro-neurogenic and neuroprotective effects in neurodegenerative and psychiatric disorder (120). NAC can cross the blood-brain barrier and mitigate age-associated memory decline (117,120). NAC may prevent ferroptosis by activating Nrf2, which regulates the expression of metallothioneins, ferritins and ferroportins, thereby preventing iron accumulation. Other Nrf2-dependent genes, including GPX4, GSH and NADPH synthesis genes, as well as epigenetic regulators of lipid hydroperoxides, contribute to its ferroptosis-inhibitory effects (117–119). In AD, NAC has potential as a GSH precursor, enhancing antioxidant defenses (120). Rat and gerbil studies have demonstrated that intraperitoneal NAC administration protects against oxidative damage induced by acrolein, peroxynitrite, hydroxyl radicals and 3-nitropropionic acid while increasing GSH levels in the brain and synaptosomes (119–123).

Curcumin, a polyphenolic compound initially identified as diferuloylmethane in turmeric rhizomes, has demonstrated protective effects against oxidative damage resulting from iron accumulation in cells (124). Curcumin treatment has been shown to decrease expression of GPX4 while increasing levels of heme-oxygenase (HO-1) and Nrf2 (124). As a key regulator of oxidative stress, Nrf2 governs the expression of ARE-dependent genes (62,125). Hirata et al (126) developed hybrid molecules that combine the oxidized indole structure of neuroprotective agents with the polyphenolic structure of curcumin, applying them to mouse hippocampal HT22 cells. These hybrids exhibited superior neuroprotective effects and lower cytotoxicity compared with curcumin alone, activated ARE, chelated ferrous ions and scavenged ROS, thereby protecting cells from oxidative stress and ferroptosis, ultimately promoting neuronal survival (104,127,128).

Lip-1, a derivative of quinoxaline spirocyclic compounds, is a potent ferroptosis inhibitor first identified in 2014 through small molecule compound library screening (129). Lip-1 primarily exerts its effects by inhibiting lipid peroxidation. Li et al (130) demonstrated that Lip-1 alleviates memory deficits in a mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. Moreover, Lip-1 reduced microglial activation and the secretion of pro-inflammatory cytokines such as IL-6 and TNF-α, while mitigating oxidative stress, lipid peroxidation, mitochondrial damage and neuronal injury following LPS exposure. Further studies have revealed that Lip-1 not only prevents mitochondrial lipid peroxidation but also restores the expression of key molecules involved in ferroptosis regulation, including GSH, GPX4 and ferroptosis suppressor protein 1 (135,136). These findings suggest that GPX4 inhibition may induce ferroptosis in oligodendrocytes, with Lip-1 serving as a potent ferroptosis antagonist. Therefore, Lip-1 holds promise as a therapeutic candidate for CNS disease (131).