Iron is an essential metal cofactor that plays a vital role in many physiological functions in the body. Various physiological processes are regulated by iron in the brain, including functions that contribute to myelin formation, neurotransmitter synthesis and antioxidant enzymes [1]. Maintaining homeostasis of iron is crucial for maintaining human health, as both iron deficiency and iron overload can be harmful. It has been demonstrated that iron is essential for the normal function of neurons, oligodendrocytes, astrocytes and microglia in the central nervous system (CNS) [2]. Abnormal iron metabolism can increase blood-brain barrier (BBB) permeability and neuroinflammation, promoting neurodegenerative processes [3]. Ferroptosis is a novel type of iron-dependent cell death caused by iron overload, which results in iron-dependent accumulation of lipid peroxides and the production of reactive oxygen species (ROS) [4]. This may be a novel mechanism for inducing neuronal death in neurodegenerative diseases such as Alzheimer’s disease (AD).

There is increasing evidence that iron overload and homeostasis dysregulation of iron contribute to neurodegeneration in AD and that dysregulation of metal homeostasis is associated with cell activation and death processes [5, 6]. In an earlier study, histochemistry showed a striking accumulation of iron (III), localized with iron (II) cyanide, which was closely related to senile plaques, neurofibrillary tangles, and neuropil threads; the iron associated with this lesion promotes in situ oxidation and catalyze H₂O₂-dependent oxidation, indicating that iron accumulation may be an important factor in oxidative damage in AD [7]. Patients with moderate cognitive impairment (MCI) and AD have higher levels of brain iron deposition, according to quantification using susceptibility-weighted imaging [8]. Further evidence suggests that disruption of iron homeostasis and elevated ferritin levels in the cerebrospinal fluid (CSF) are linked to the progression from MCI to AD [9]. Additionally, a meta-analysis involving 2174 patients with AD and 2931 healthy controls showed decreased levels of iron in the blood and increased ferritin in the CSF of patients with AD when compared to levels in controls, suggesting that iron and iron-associated proteins are associated with the risk of AD [10]. Notably, whole-exome sequencing identified protein-coding variants associated with brain iron in 29,828 individuals, revealing several insights into the relationship between brain iron accumulation and AD and identifying multiple genes associated with brain iron accumulation levels [11]. These studies demonstrated a strong correlation between the pathophysiology of AD and iron homeostasis disturbance.

Recently, most research on iron-mediated neurodegenerative diseases has focused on neurons, ignoring the role of non-neuronal cells, in regulating pathological processes. Indeed, in an environment of iron metabolism disorder AD, the crosstalk between glial cells and neurons may form positive feedback, astrocyte reactive hyperplasia and amyloid-beta peptide (A$\beta$) activation of microglia, resulting in a self-amplifying inflammatory response in the AD process [2, 12, 13]. This suggests that iron deposition-induced ferroptosis, glial cell activation and neuroinflammation may be potential underpinnings of AD pathogenesis.

AD is a neurodegenerative disease that stands out as a prominent health problem for elderly individuals worldwide. It has become evident that AD is not only linked to its hallmark lesions—the accumulation of A$\beta$ and development of neurofibrillary tangles (NFT) consequent to the hyperphosphorylation of tau protein but also to other concurrent pathologies [14]. Currently, the exact pathogenesis of AD is complex and still not fully understood, as it is influenced by factors such as genetics, aging, nutrition and a person’s environment [15]. The complexity of the clinical measurement of underlying pathogenesis also poses a challenge to characterizing the pathology of AD and the fact that most medications only alleviate the symptoms and usually fail to achieve the desired outcome [15]. Indeed, the underlying biological mechanisms implicated in the pathogenesis of AD are also involved in abnormal protein dynamics, oxidative stress, neuroinflammation, disturbances of metal-ion homeostasis and bioenergetics [16].

Aberrant iron uptake, excretion and storage in neurons increases intracellular labile iron pools (LIP) and Fenton responses during the regulation of iron homeostasis [17]. The primary regulator of intracellular iron metabolism is the iron regulatory protein (IRP) response element (IRE) regulatory system [18]. In an intracellular environment deficient in iron, IRP binds to ferritin and homologous IRE in the untranslated region of transferrin receptor 1 (TfR1) mRNA to promote ferritin mRNA translation inhibition and stabilize TfR1 mRNA to prevent intranuclear catabolic events [19]. However, in iron-rich cells, IRP does not bind to the IRE, enhances ferritin synthesis, permitting degradation of TfR1 mRNA and the extracellular transport of Fe³⁺ by transferrin (Tf) to cells, subsequently reducing Fe²⁺ [20, 21]. Fe²⁺ are then transported from endosomes to the cytoplasm via divalent metal transporter 1 (DMT1), which is regulated by homeostasis of LIP [22]. DMT1 is used for normal neuronal metabolism and is partially stored in ferritin to protect neurons from excess iron [23]. When excess H₂O₂ in the cell interacts with Fe²⁺, it starts the Fenton reaction, which causes intracellular lipid peroxidation to produce ROS and ferroptosis [24]. Notably, iron export in neurons is mediated by iron-exporting transmembrane protein ferroportin1 (Fpn1) through the Fpn1/Hephaestin and Fpn1/Ceruloplasmin (CP) pathways [25, 26]. Alterations to this pathway induce iron retention, leading to memory impairment [27, 28]. Simultaneous Fe²⁺ and Fe³⁺ imaging shows their enrichment in the brains of mice with AD [29]. Moreover, increased ferritin heavy chain (FTH) and ferritin light chain expression were found in the brains of AD patients, suggesting that LIP is increased in AD, confirming that iron can be used as a biomarker for AD [5].

A$\beta$ deposition and hyperphosphorylated Tau protein tangles are AD’s two main pathological features. Autopsy and magnetic resonance imaging have shown significant iron deposition around senile plaques [30] and at sites of cortical Tau accumulation [31], suggesting potential crosstalk between iron and senile plaques and neurogenic fiber tangles. Iron-A$\beta$ complexes are formed in the Amyloid Precursor Protein (APP)/Presenilin genes 1 (PS1) animal, as shown by submicron resolution X-ray microscopy, indicating a direct correlation between A$\beta$ and iron [32]. A$\beta$ is produced by the amyloid precursor protein (APP) and an IRE in the 5^′ untranslated region of the APP transcript regulates APP levels [33]. It has been shown that higher cellular iron levels in AD pathology cause increased APP translation and A$\beta$ generation [34]. Interestingly, APP can interact with and stabilize Fpn1 to facilitate iron export and maintain the homeostasis of iron concentration [35]. Silencing/mutation of APP leads to abnormal Fpn1 function and inefficient neuronal output of iron, which further leads to iron accumulation, suggesting that APP/Fpn1 plays an important role in the regulation of iron homeostasis in the brain [36]. Furthermore, in the context of aging, Fpn1 exhibits age-dependent down-regulation [37], as demonstrated in the APPswe/PS1dE9 mouse model and in brain tissue from AD patients [28]. The degradation of APP involves two pathways, mainly involving three secretases: $\alpha$, $\beta$, and $\gamma$ [38]. Under normal physiological conditions, APP is processed by $\alpha$-secretase to produce non-toxic forms of P3, A$\beta$16 and A$\beta$17-40/42; on the downside, when iron is overloaded in cells, $\beta$ and $\gamma$ secretases promote APP cleavage to form A$\beta$1-40 and A$\beta$1-42 fragments, leading to neurotoxic amyloid proteins, inducing cell damage and death [39]. It is also noteworthy that A$\beta$ also promotes the reduction of Fe³⁺ to Fe²⁺ to be a potential source of low-oxidation-state iron, leading to oxidative damage to A$\beta$ and surrounding molecules and further deposition of A$\beta$ into senile plaques [40]. Additionally, the affinity of A$\beta$ for iron increases after aggregation, leading to additional neuronal cytotoxicity [41]. The above studies suggest that AD pathophysiology is significantly influenced by the interplay between APP, A$\beta$ and iron metabolism.

The tau protein is a significant component of neurogenic fibrillary tangles, mediating iron efflux from cells and excess iron colocalizes with tau in neurogenic fibrillary tangles [31]. Autopsy study finds colocalization of iron and tau in neurons carrying NFT associated with progressive neurodegeneration [42]. Neuronal iron overload causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3$\beta$, cyclin-dependent protein kinase-5 and mitogen-activated protein kinases amongst others, inhibiting protein phosphatase 2A [43, 44], while treatment with the iron chelator desferrioxamine alleviates iron-induced tau hyperphosphorylation [45]. Under normal physiological conditions, tau protein can transport APP to cell membranes, thereby stabilizing Fpn1 and promoting iron efflux [46]. However, due to over-modification and cleavage of APP by secreted enzymes, APP is unable to reach the cell surface properly, which results in a decrease in Fpn1 levels and iron accumulation within neurons and NFT [47, 48]. Notably, increased levels of oxidative stress mediated by iron regulatory imbalance may also promote tau oligomerization by binding to cysteine containing mercapto-cysteine [49]. Moreover, in a cell culture model, iron may lead to hyperphosphorylation and aggregation of tau proteins through iron binding motifs in tau proteins as well as dysregulation of insulin signaling [50]. More importantly, it has been demonstrated that age-induced neurodegeneration is caused by iron accumulation in the cortex, substantia nigra and hippocampus of tau mutant mice [47]. APP/PS1 mice with iron feeding showed impaired cognitive function, accompanied by increased in A$\beta$ accumulation and phosphorylation of tau expression [51]. Inhibition of iron-induced hippocampal tau phosphorylation [52] and APP production processing in APP/PS1 mice is induced by treatment with the iron chelator desferrioxamine (DFO), thereby inhibiting A$\beta$ deposit formation [53] and reversing iron-induced memory impairment [52]. Different models of AD show a strong association between iron accumulation with A$\beta$ deposition and tau phosphorylation. However, the up- and downstream molecular mechanisms among these three in this potentially relentless cycle remain unclear. Despite insufficient data from human studies, targeting iron homeostasis with therapies improves AD pathology, as one important mechanism controlling the early pathological development of AD is iron metabolism.

Dysregulation of iron metabolism in AD has been demonstrated mainly in preclinical studies. Studies have found that Fpn1 is downregulated in AD patients and APP/PS1 animal models, while genetic absence of Fpn1 resulted in hippocampus atrophy and memory impairment. However, administration of specific iron chelating inducer significantly reduces neuronal death and memory deficits caused by A$\beta$ aggregation, while restoration of Fpn1 ferroptosis and memory deficits in APP/PS1 mice [28]. Additionally, ferritinophagy-mediated ferroptosis is a key mechanism leading to neurodegenerative disease [54]. An essential component of the body’s regulation of iron metabolism is the iron store protein ferritin; nuclear receptor coactivator 4 (NCOA4) and ferritin-containing iron cooperate in iron-deficient cells to mediate the release of iron from the ferritin storage pool through the ferritinophagy pathway [55]. The ferritinophagy process promotes ferroptosis and ferritin degradation within the lysosome and dysfunction of ferritinophagy is an important factor contributing to iron accumulation in senescent cells, this can lead to elevated total iron levels within affected brain regions, especially in AD pathology [56, 57].

Calcium-mediated oxidative stress is largely inseparable from iron, as both iron and Ca²⁺ play key roles in neuronal function, such as ROS production, mitochondrial homeostasis, and synaptic plasticity [58]. Iron-induced neuronal ROS production alters Ca²⁺ signaling, which in turn affects synaptic plasticity and hippocampus-dependent memory formation [59, 60]. In the mouse hippocampal neuronal cell line HT-22, excess iron leads to mitochondrial fragmentation and increased Ca²⁺ levels, which in turn stimulates the Ca²⁺-dependent phosphatase calcineurin and neuronal cell death [61]. In primary hippocampal neurons, iron-induced ROS increase promotes the release of calcium in the endoplasmic reticulum (ER) and subsequent mitochondrial fission may lead to neuronal dysfunction [62]. Thus, mitochondria as a potential target for the treatment of neurodegenerative processes induced by abnormal iron metabolism. Notably, the crosstalk between iron, ROS, and Ca²⁺ signaling is bidirectional, as many proteins involved in cellular antioxidant defense and ROS production are dependent on Ca²⁺. The aberrant increase in intracellular Ca²⁺ promotes the uptake of mitochondrial Ca²⁺ by mitochondrial Ca²⁺ unidirectional transporters, resulting in more ROS production, which may further increase an unstable iron pool [63]. A primary hippocampal neuronal study has reported an influx of iron through Ca²⁺ channels, resulting in altered intracellular iron content [64]. A sustained increase in Ca²⁺ flux regulates the immunological profile of ferroptosis [65]. Overall, current evidence suggests that the coordinated interrelationship between excess iron and abnormal Ca²⁺ signaling is most likely to occur in neurodegeneration, particularly AD, as abnormal calcium signaling is a central issue in AD pathology [66, 67, 68].

Several pathological features found in AD patients are highly correlated with ferroptosis, including elevated levels of free iron [8], lipid peroxidation [69] and defects in antioxidant systems such as glutathione peroxidase 4 (GPX4), glutathione (GSH), and cystine/glutamate antiporter system (system Xc^–) [70]. System Xc^–, composed of the light chain Solute Carrier Family 7 Member 11 (SLC7A11) and heavy chain Solute Carrier Family 3 Member 2 (SLC3A2), is an important glutamate transporter in the CNS for the cellular uptake of cystine in exchange for intracellular glutamate [71]. In the context of AD, compensatory uptake of cystine leads to poor glutamate clearance in the synaptic cleft, causes excitatory neurotoxicity through system Xc^–, enhances lipid peroxidation and leads to ferroptosis and the development of AD [72, 73]. Additionally, GSH is an important intracellular antioxidant that prevents iron-dependent oxidation, which is a crucial biological process in ferroptosis, primarily by binding to Fe²⁺ in unstable LIP [74]. Reduced GSH levels have been found in the occurrence and progression of AD [75]. Further, $\gamma$-glutamylcysteine ethyl ester, a precursor to GSH, was found to increase intracellular GSH content, thereby inhibiting neuronal toxicity triggered by an A$\beta$-induced decline in GSH levels [76] and these findings suggest a strong link between dysregulation of GSH levels and AD pathology. Another predisposing factor associated with ferroptosis in AD is GPX4. GPX4 has been shown to be a key regulatory enzyme in AD-associated ferroptosis and has been shown to repair lipid hydroperoxides in membranes and inhibition of GPX4 is one of the key factors in the pathogenesis of ferroptosis-associated AD [77]. Indeed, knockout of the GPX4 gene in the brain leads to a number of features associated with AD pathology, for example, Gpx4BIKO mice exhibit cognitive deficits and hippocampal neurodegeneration, including reduced levels of NeuN, synaptophysin and Synaptosome Associated Protein 25 (SNAP25) and a significant decline in learning ability and memory in mice over time [78]. Additionally, studies have shown that GPX4 deletion upregulates $\beta$-secretase activity and leads to increased A$\beta$ production [79], overexpression of the GPX4 gene in 5xFAD mice reduced cognitive impairment and markedly enhanced learning and memory [77]. Further, mutations in presenilin genes 1 and 2 (PS1 and PS2) mediate autosomal dominant familial AD lesions; mutations in PS1 and PS2 cause AD lesions by repressing GPX4 expression and deregulating ferroptosis [80]. These findings suggest that ferroptosis is involved in AD lesions and the search for drugs t targeting Xc^–, GSH and GPX4 systems represents an important direction in AD research. Notably, the aging brain expresses high quantities of polyunsaturated fatty acids, which are favored substrates for lipid peroxidation during ferroptosis and increase vulnerability to the consequences of ferroptosis [81]. Moreover, one important regulator of ferroptosis is nuclear factor erythroid 2-related factor 2 (Nrf2), Nrf2 activates to protect cells and tissues from ferroptosis by regulating significant genes, such as those involved in iron and glutathione metabolism, against oxidative stress caused by excess iron [82]. Research has demonstrated that Nrf2 mRNA expression is significantly lower in AD patients and animal models, and that Nrf2 deficiency speeds up the production of A$\beta$ and $\beta$-secretase 1 (BACE1) expression [83]. More importantly, the expression of Nrf2 decreases with age, suggesting that it may contribute to the development of AD by promoting ferroptosis stress sensitivity [84].

Apolipoprotein E (APOE) allele variants are the most significant genetic risk for disseminated AD and APOE variants, leading to A$\beta$ deposition, hippocampal atrophy and abnormal brain metabolic function [85]. Ferritin levels in CSF have been found to be positively correlated with APOE-$\epsilon$4 expression and negatively correlated with both MCI and AD [86]. In this context, Duro et al. [87] found an association between APOE-$\epsilon$4, intracortical iron and brain function. Indeed, elevated extracellular iron levels upregulate APOE-$\epsilon$4 expression in neurons and accelerate intracellular polyunsaturated fatty acids (PUFA) accumulation [88], providing a suitable environment for lipid peroxidation and ferroptosis, which leads to increased extracellular A$\beta$ deposition and exacerbation of AD [89]. Notably, glial cell dysfunction is thought to contribute to amyloid accumulation and synaptic loss in AD and Haney et al. [90] found that both a large number of lipid droplets accumulate in glial cells and their synaptic pruning function may be regulated by the APOE allele. Moreover, a recent research has revealed that APOE is a potent inhibitor of ferroptosis that activates the Phosphatidylinositol-3-kinase/ Protein kinase B (PI3K/AKT) pathway and inhibits the autophagic degradation of ferritin (ferritinophagy) thereby avoiding lipid peroxidation mediated by iron [57]. Although the study of APOE in brain iron regulation needs to be further developed, iron seems to provide a bridge between APOE and AD, which supports a further theoretical basis for the study of the pathomechanisms of AD.

Ferroptosis in AD is accompanied by multiple pathologic changes. A variety of other manifestations associated with ferroptosis have been identified in various neurological diseases mediated by neuroinflammation, and damage-associated molecular patterns. These include the ROS generated during ferroptosis events that activate glial cells by activating neuroimmune pathways, which subsequently lead to the production of various inflammatory cytokines that promote the development of neurological diseases [91]. Novel drugs that target inflammation have shown effective intervention against ferroptosis. One study found that dimethyl fumarate attenuates neuroinflammation and ferroptosis by mediating the inflammatory central node nuclear factor-$\kappa$B (NF-$\kappa$B) signaling pathway and ameliorates bivascular occlusion-induced cognitive impairment in rat chronic cerebral hypoperfusion models [92]. Similarly, silybin exerts neuroprotective effects on STZ-induced sporadic AD models by downregulating ferroptosis injury and thereby downregulating downstream stimulator of interferon genes (STING)-mediated neuroinflammation [93]. Indeed, a recent study indicates that ferroptosis is associated with the activation of inflammation, including the activation of multiple inflammation-related signaling pathways, including the Janus kinase-signal transducer and activator of transcription (JAK-STAT), NF-$\kappa$B, inflammasome, cyclic Guanosine Monophosphate–Adenosine Monophosphate (GMP-AMP) synthase-stimulator of IFN genes (cGAS-STING) and Mitogen-Activated Protein Kinase (MAPK) pathways [94]. Targeting these inflammation-related pathways may provide intervention for ferroptosis, especially in AD, as one of the important features of AD pathogenesis is neuroinflammation [95].

Various pathways, including iron metabolism, redox status, lipid and sugar metabolism, the metabolism of cytotoxic amino acids and mitochondrial activity may regulate the process of ferroptosis [4]. Major markers of ferroptosis, dysregulation of ferritosis, lipid peroxidation and ROS production have long been identified in the brain and animal models of AD patients [96]. A recent transcriptomic study has identified differential expression of genes associated with ferroptosis in AD in different glial cells and neurons [97], suggesting that the pathogenic process of ferroptosis in AD may include glial cells. Though it’s yet unknown exactly how ferroptosis occurs in neurons, non-neuronal cells such as glia are integral to mediating ferroptosis to neurons [17]. When activated, glial cells can induce ferroptosis by disrupting iron homeostasis, releasing proinflammatory factors, altering amino acid metabolism and raising levels of oxidative stress, which are associated with many organ injuries and degenerative diseases [98, 99]. For instance, neurofilament light chain, a pathologic marker for various neurological disorders, including AD, is part of the axonal cytoskeletal protein complex and FTH may be released into the extracellular space while reflecting the senescent state of microglia. After acting on microglia with various neurofilament light chain concentrations, the secretion of FTH-containing exosomes by microglia increased and stimulated peroxidation of membrane lipid and neuronal loss involved in neuronal ferroptosis [100]. Although iron homeostasis and ferroptosis are crucial in causing AD neuronal death, how they interact and lead to neurodegeneration remains poorly understood. Therefore, the pathological processes of iron metabolism disruption and associated cell death urgently require further investigation in the brain.

Microvascular endothelial cells (BMECs), astrocytes, microglia and pericytes together constitute the BBB [101]. The BBB is an effective protective filter for the brain as it regulates iron entry, separating cerebral iron homeostasis from whole-body homeostasis. Expressed on the luminal side of cerebral capillaries, TfR1 mediates iron uptake in the brain and binds circulating transferrin to promote the transfer of iron to BMECs through the TfR1-mediated endocytosis mechanism [3]. Notably, hepcidin is a peptide hormone implicated in the regulation of Fpn1 and brain iron metabolism. It has been shown that hepcidin is expressed in cortical neurons, glial cells and BMECs and plays an important role in the regulation of iron homeostasis [102]. Hepcidin binds to Fpn1 in the cell membrane of BMECs, promotes the internalization and degradation of Fpn1 and blocks the passage of iron into the brain through the BBB [103]. It was shown that hepcidin expression levels were reduced in AD patients and APP transgenic mice, whereas hepcidin treatment of cultured BMECs and neurons resulted in a reduction of iron input (TfR1 and DMT1) and output (Fpn1) proteins, which reduced iron uptake in neurons [104]. Furthermore, in a recent study of the APP/PS1 mouse model, it has been shown that hepcidin overexpression in astrocytes induces a reduction in iron levels in cortical and hippocampal neurons, with significant improvements in cognition and A$\beta$ plaque aggregation, leading to a reduction in oxidative stress and neuroinflammation, but more importantly, a reduction in neuronal death [105]. Additionally, it was found that iron, transferrin and ferritin levels in astrocytes, microglia and oligodendrocytes change during aging [106]. This means that glial cells play an important role in the regulation of iron in the brain. In fact, aging mediates inflammation and BBB damage, which is responsible for the uneven and unbalanced distribution of brain iron and the main cause of neurodegeneration, while aging-dependent brain iron accumulation may be due to changes in ferritin levels that impair its homeostasis, which in turn activates glial cells, induces cytokine release and propagates neuroinflammation.

Glial cells are not only the primary support cells for neurons but are active participants in neuronal network formation and information processing in the CNS [107]. Extensive research has demonstrated that the crucial role of ferroptosis in the inflammatory response. Ferritin synthesis is regulated by proinflammatory cytokines, including interleukin-1$\beta$ (IL-1$\beta$), interleukin-6 (IL-6), tumor necrosis factor $\alpha$ (TNF-$\alpha$), and interferon-gamma (IFN-$\gamma$), which affect iron storage in cells and tissues [108]. Microglia first induce ferroptosis and may do so by producing inflammatory factors, including interleukin-8 or IL-1$\beta$ [109]. Astrocyte-neuron interactions protect neurons from ferroptosis, these include enhanced expression of GSH, Nrf2 and catalase to counteract redox stress associated with excess free iron [110, 111]. For example, in the resting state, the ferroptosis inhibitor Nrf2 is efficiently activated by brain-derived neurotrophic factor in astrocytes and regulates metabolic cooperation between astrocytes and neurons [112]. Thus, dysregulation of neuronal interactions in astrocytes may induce neuronal ferroptosis. Additionally, in the setting of iron deficiency, astrocytes and microglia are able to release iron bound to ferritin and support oligodendrocytes during myelination [113, 114]. Conversely, in the setting of iron overload, oligodendrocytes overexpress ferritin, providing important antioxidant defenses to neurons [115]. Uncontrolled glial activation and neuroinflammation are involved in the pathogenesis of AD [116]. In the brains of AD patients, reactive astrocytes accumulate around A$\beta$ by phagocytosis of locally degenerated dendrites and synapses [117] and surround A$\beta$ deposition in the form of glial scars [118]. Activated microglia and astrocytes induce neuronal death in vitro by releasing proinflammatory factors, nitric oxide (NO), ROS, and glutamate [119]. Moreover, in sporadic and preclinical AD patients, focal loss of oligodendrocytes in the neocortical gray matter is associated with A$\beta$ plaque cores [120]. Indeed, glial cells regulate iron metabolism by expressing iron regulatory proteins to maintain normal myelin sheath function and neuronal recombination processes; when activated, they can influence AD pathology by inducing neuronal death through pathological processes such as disruption of iron homeostasis [2], release of various cytokines, alteration of protein metabolism, and increased levels of oxidative stress (Fig. 1). Thus, there is a need to gain insight into the interactions between glial cells and iron metabolism and neurodegenerative diseases, which may facilitate the exploration of therapeutic strategies for AD by restoring iron homeostasis and inhibiting oxidative stress.

Fig. 1.

Molecular mechanisms of glial cell ferroptosis regulation in AD. In an AD pathological setting, glial cells are exposed to elevated levels of iron, lipopolysaccharide and extracellular A$\beta$ released by damaged neurons. (i) DMT1 and ferritin expression are upregulated in microglia, leading to increased intracellular iron stores. With continued iron uptake, LIP is formed. Iron induces ROS production and activates inflammatory factor release, promoting neuroinflammation, infiltrating A$\beta$ plaques and promoting neuronal iron accumulation. Increased iron promotes microglia glycolytic pathways, reduces phagocytosis and leads to A$\beta$ deposition. Extracellular A$\beta$ promotes ROS production via NADPH-oxidase, further increasing DMT1 expression and promoting iron sequestration, forming a relentless cycle of iron, ROS and A$\beta$. (ii) High iron levels induce reactive astrocytes to produce ROS and release inflammatory factors to promote A$\beta$ deposition and NFT formation. Inflammatory factors upregulate DMT1 expression and downregulate Fpn1 expression, further promoting iron sequestration. Hepcidin in astrocytes resist ROS-mediated inflammatory factor release and upregulate Fpn1 expression. CP protein regulates the dynamic balance of iron entering and leaving the cell. (iii) Activated oligodendrocytes release ROS to promote neuronal oxidative stress, upregulate ferritin expression, increase intracellular iron stores and provide antioxidant defense against iron-induced cytotoxicity by secreting ferritin heavy chains. Three types of glial cells change neuronal iron homeostasis in neuroinflammation, promote iron accumulation in neurons by releasing inflammatory factors, infiltrating A$\beta$ plaques and NFT formation, triggering neuronal ferroptosis, resulting in neuronal loss. Abbreviations: ROS, reactive oxygen species; HO-1, heme oxygenase 1; DMT1, divalent metal transporter 1; NOX, NADPH-oxidase; LPS, lipopolysaccharide; IFN-$\gamma$, interferon-$\gamma$; TNF-$\alpha$, tumor necrosis factor $\alpha$; IL-1$\beta$, interleukin-1$\beta$; IL-6, interleukin 6; iNOS, inducible nitric oxidesynthase; Lf, lactoferrin; APP, amyloid precursor protein; A$\beta$, amyloid $\beta$-protein; NFT, neurofibrillary tangles; LIP, labile iron pool; Lipro-1, liproxstatin-1; FTH, ferritin heavy chains; BChE, butyrylcholinesterase; AChE, acetylcholinesterase; TGF-$\beta$1, transforming growth factor-$\beta$1; NOX4, NADPH Oxidase 4; GPI-CP, glycosylphosphatidylinositol-anchored proteins; MTFT, Mitochondrial ferritin; Fpn1, ferroportin1; TfR, transferrin receptors. This figure was drawn using Biorender (https://www.biorender.com).

Given an aging population, early detection of AD is essential. Notwithstanding substantial progress in understanding the etiology of AD, drug development therapeutic strategies based on these discoveries have very limited efficacy in altering the course of the disease. Consequently, there are compelling reasons to investigate new therapeutic approaches. Ferroptosis research has recently made rapid progress in understanding the pathophysiology of AD. Dysregulation of brain iron homeostasis exacerbates neurotoxicity and cognitive impairment. Thus, targeted ferroptosis inhibitors gain new momentum in the treatment of AD. Nevertheless, further study is required to pinpoint the exact cause of neurodegenerative diseases linked to ferroptosis. The current review elucidates the function of iron homeostasis between neuronal and glial cells in AD pathogenesis. Disturbed iron metabolism in glial cells mediates inflammation, oxidative stress and other pathological processes damaging neurons; iron deposition in neurons also leads to glial cell hyperactivation, accompanied by the release of proinflammatory factors and iron metabolism molecules by overactive microglia and astrocytes, mediating neuronal cell death in AD pathology. There are few studies on the mechanism of ferroptosis in oligodendrocytes in AD. Oligodendrocytes are high in iron content and tightly wrapped around neuronal axons; further study is necessary to investigate the ferroptosis induced by oligodendrocytes in AD neurons during aging.

In summary, ferroptosis is involved in the interaction between glial cells and neurons, thereby regulating the pathogenesis of AD. However, experimental animal models are the primary focus of current ferroptosis research and changes in ferroptosis in AD patients cannot be fully simulated. Comprehensive preclinical investigations are necessary to completely understand the precise molecular and cellular pathways of iron metabolism in AD neuronal degeneration, even while clinical trials assess the potential treatment benefits focused on ferroptosis.

YY and WD conceived the perspective of the work. JX, RS, MQ, and BX drafted the manuscript. JX, ZZ, BX, and YJ designed the figure. RS and MQ collect and sort references. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

This work was supported by the National Natural Science Foundation of China (31871031, WD), Ministry of Science and Technology of the People’s Republic of China (2019YFE0120600), and Sichuan Science and Technology Program (2023NSFSC0593, YY; 2022YFS0615, BX), the Science and Technology Planning Project of Luzhou (2022-JYJ-140 to YY).

The authors declare no conflict of interest.