The Xc⁻/GSH/GPX4 axis constitutes the primary intracellular antioxidant defense mechanism against ferroptosis. This axis comprises the cystine/glutamate antiporter system Xc⁻, GSH and GPX4, which function sequentially to maintain phospholipid redox homeostasis (Fig. 4). System Xc⁻ serves as the initial step of this defense axis. It is a heterodimeric transport complex composed of heavy chain solute carrier family 3 member 2 (SLC3A2; 4F2hc) and light chain SLC7A11 (xCT) (27). It exchanges intracellular glutamate with extracellular cystine in a 1:1 ratio. Upon cellular uptake, cystine is reduced to cysteine, which is a precursor for GSH synthesis. The selenoenzyme GPX4 utilizes GSH as a substrate to reduce toxic lipid hydroperoxides into nontoxic lipid alcohols, thereby playing a critical role in defending against ferroptosis (28). Impairment of any component of this protective axis markedly increases cellular susceptibility to ferroptosis. For instance, erastin inhibits system Xc⁻ activity, thereby blocking cystine uptake, depleting GSH and inducing ferroptosis (29). Conversely, the RAS-selective lethal compound 3 directly inhibits GPX4 activity, leading to uncontrolled lipid peroxide accumulation, membrane damage and ferroptosis (30).

Oxidation of polyunsaturated fatty acids (PUFAs) containing bis-allylic hydrogen atoms, such as arachidonic acid and adrenic acid, is a hallmark of ferroptosis (Fig. 4). First, PUFAs must be activated and esterified into membrane phospholipids. This process is initiated by acyl-CoA synthetase long-chain family member 4 (ACSL4), which converts free PUFAs into their acyl-CoA esters (PUFA-CoAs), a prerequisite for their incorporation into membrane lipids (31). As the primary enzyme that loads PUFAs into phospholipids, ACSL4 determines the cellular abundance of PUFA-containing membrane lipids, thereby establishing the membrane's intrinsic sensitivity to lipid peroxidation and ferroptosis. Lysophosphatidylcholine acyltransferase 3 catalyzes the remodeling of PUFA-CoAs into membrane phospholipids, generating PUFA-containing phospholipids (PUFA-PLs) (32). Membrane-integrated PUFA-PLs serve as direct substrates for lipid peroxidation. Lipoxygenases (LOXs), particularly 15-LOX, are highly selective for PUFA-PLs, including arachidonoyl phospholipids, and oxidize them to phospholipid hydroperoxides (PL-OOH). By contrast, large quantities of ferrous iron released from ferritin via ferritinophagy can efficiently promote the oxidation of PUFA-PLs to PL-OOH by generating high levels of ROS through the Fenton reaction. GPX4 is the key enzyme that prevents ferroptosis by catalyzing the reduction of PL-OOH to their corresponding non-toxic PL-OH, using GSH as a cofactor. Once formed, if not promptly reduced by GPX4, PL-OOH reacts with adjacent PUFA-PLs, initiating a self-amplifying positive feedback cycle of lipid peroxidation. This uncontrolled chain reaction ultimately leads to irreversible disruption of membrane integrity and cell death (30).

Nrf2 is a key transcription factor regulating the cellular OS response, and many of its downstream target genes are directly involved in the regulation of ferroptosis (Fig. 3). These genes encompass proteins related to iron metabolism (such as FTH1 and FPN) and core antioxidant components (including GPX4, SLC7A11 and the GSH synthesis pathway). Under homeostatic conditions, the Neh2 domain of Nrf2 interacts with Keap1 via its ETGE and DLG motifs, leading to constitutive ubiquitination and degradation of Nrf2 and negative regulation of this pathway (33). When the cell encounters OS, such as that triggered by the Fenton reaction between cytosolic free Fe²⁺ and H₂O₂, which generates highly reactive hydroxyl radicals (·OH), Keap1 dissociates from Nrf2, allowing stable Nrf2 to accumulate and translocate into the nucleus. Inside the nucleus, Nrf2 binds to the ARE and recruits transcriptional coactivators such as cAMP response element-binding protein-binding protein/p300. Specifically, the Neh4 and Neh5 domains of Nrf2 interact with the TAZ1 and TAZ2 domains of CBP/p300, acting as a scaffold to facilitate chromatin remodeling and assembly of the transcription machinery (34). This interaction robustly initiates the transcription of its target genes. By upregulating FTH (enhancing iron storage) and FPN (promoting iron efflux), Nrf2 effectively reduces the intracellular labile iron pool. These two responses are not contradictory but form a balanced, coordinated strategy to mitigate iron toxicity. Simultaneously, Nrf2 directly enhances the cellular antioxidant capacity by positively regulating GPX4, thereby synergistically suppressing neuronal ferroptosis. The activity of this pathway is finely regulated by BTB and CNC homology 1 (BACH1). BACH1 competes with Nrf2 to bind ARE sequences, thereby repressing the transcription of Nrf2 target genes (35). In OS, BACH1 is inactivated, which relieves its transcriptional repression and consequently promotes an Nrf2-driven antioxidant response.

AD neuropathology is characterized by extracellular Aβ plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Aβ plaques arise from aggregation of Aβ1-40/42 peptides derived from Aβ protein precursor cleavage, whereas NFTs result from the accumulation of phosphorylated tau (p-tau). Dysregulated iron metabolism in AD brains leads to pathological iron deposition in regions such as the hippocampus and cortex. Excess iron induces OS via Fenton reactions, promoting Aβ aggregation and tau hyperphosphorylation. Lactylation of the tau protein at the K677 site was found to confer neuroprotection in an AD mouse model. This modification acts by suppressing p38 mitogen-activated protein kinase-mediated ferritinophagy, thereby reducing iron release and mitigating ferroptosis and neuroinflammation (36). It should be noted that this protective effect has so far been demonstrated only in a mouse model. Thus, validation in human post-mortem brain tissues and other experimental systems is essential to confirm its pathophysiological relevance in patients with AD. These findings indicate that tau lactylation is a promising therapeutic target. Aβ is generated via β-secretase and γ-secretase cleavage of amyloid precursor protein. Mutations in presenilin (PSEN), which are linked to familial AD, impair γ-secretase activity. PSEN mutations exacerbate oxidative damage by blocking γ-secretase-mediated upregulation of FTH/FTL under iron challenge, implicating γ-secretase in IRP-IRE-regulated iron metabolism (37).

Iron is essential for myelination, synaptic plasticity, oxidative metabolism and neurotransmitter synthesis in the CNS (38). Iron overload contributes to ferroptosis, OS and neuroinflammation, disrupting the CNS microenvironment. During this process, hepcidin, which is primarily secreted by hepatocytes, maintains systemic iron homeostasis by suppressing the iron export function of FPN, the only known iron exporter. This regulatory process is corroborated in the context of AD. Analysis of the cingulate cortex from Braak stage III-VI patients with AD by Chaudhary et al (39) demonstrated that upregulated hepcidin transcription leads to decreased FPN expression, resulting in increased ferritin levels and elevated total brain iron content. It is generally thought that the upregulation of hepcidin is triggered by IL-6 released from activated glial cells or peripherally derived IL-6 transport - that is, inflammation induces hepcidin upregulation (40). However, it has not been ruled out that hepcidin upregulation may represent a physiological feedback response to early, localized iron overload.

Ferritin co-localizes with Aβ plaques in AD brains (41). In healthy brains, FTH is predominantly found in the oligodendrocytes and astrocytes (41). In AD mouse hippocampi, FTH1 mRNA accumulates in astrocytic somata, whereas FTL1 mRNA redistributes to thickened astrocytic processes near Aβ deposits, suggesting spatial regulation of iron homeostasis under physiological and pathophysiological conditions (12).

Activated microglia located near neuritic plaques exhibit robust ferritin expression (42). Neuritic plaques comprise neurons, microglia and Aβ, though their pathogenesis is incompletely understood. Microglial ferritin (iron sequestration) and Aβ (iron chelation) may synergistically promote plaque formation (43). FTL⁺ ionized calcium-binding adapter molecule 1⁺ microglia, a major Aβ-plaque-infiltrating subset, are elevated in patients with AD (44). Microglial activation coincides with ferritin upregulation, suggesting that iron storage modulates neuroinflammatory microenvironments in AD (45). Although AD involves concurrent iron accumulation and neuroinflammation, it remains unclear whether microglial iron retention and ferritin expression result from elevated iron levels, inflammatory activation or both. A study using human induced pluripotent stem cell-derived microglia revealed that microglial ferritin is regulated by iron rather than by inflammation; iron-laden microglia suppress pro-inflammatory responses but induce OS (46).

Apolipoprotein E (ApoE) is a major genetic risk factor for AD, and its role in the disease process may be closely linked to intracellular iron metabolism and tau pathology. Mice with the ApoE4 genotype exhibit significantly diminished ferritin expression in the CA1 and hippocampal regions and reduced FPN levels in the hippocampus (47). The decrease in ferritin levels may compromise the intracellular iron-binding capacity, whereas reduction in FPN restricts cellular iron export. Collectively, these alterations contribute to neuronal iron overload, which, in turn, drives the toxic accumulation of hyperphosphorylated tau. ApoE can activate the PI3K/AKT signaling pathway and inhibit the autophagic degradation of ferritin, a process known as ferritinophagy (48). This process reduces iron-dependent lipid peroxidation and maintains cellular iron homeostasis. By contrast, p-tau, a major component of NFTs, is significantly elevated in the cerebrospinal fluid (CSF) of patients with AD. Increased ferritin levels in the CSF of these patients are correlated with p-tau181, and this association is significantly mediated by CSF ApoE levels (49). These findings suggest that ApoE may indirectly influence tau phosphorylation and aggregation by regulating iron metabolism pathways. However, the precise molecular mechanisms underlying the interactions between ApoE, ferritin and tau hyperphosphorylation require further investigation.

PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, and iron dysregulation plays a central role in this process. Pathological iron deposition and α-Syn aggregation form a vicious cycle in the brain of patients with PD and drives neuronal damage. Furthermore, toxic interactions between iron and α-Syn can induce cellular senescence, a process that may precede overt neuronal loss (50). At the molecular level, this interaction triggers ferroptosis, an iron-dependent form of regulated cell death. For instance, microRNA (miR)-335 exacerbates ferroptosis by suppressing FTH1 expression, thereby increasing intracellular Fe²⁺ levels (51). However, the precise extent of FTH1 reduction by miR-335 remains to be quantified. By contrast, the neuroprotective hormone melatonin (MT) counteracts α-Syn-induced ferroptosis through MT1 receptor-mediated activation of the Sirtuin 1/Nrf2/heme oxygenase-1/GPX4 signaling axis (52).

Iron dysregulation exhibits cell-type-specific manifestations. In microglia, iron accumulation is closely correlated with neuroinflammation, as evidenced by the positive association between microgliosis and iron load in the postmortem PD substantia nigra (53). Pathogenic mutations in leucine-rich repeat kinase 2, such as G2019S, disrupt iron handling by impairing the function of its substrate Ras-associated binding protein 8a, leading to significantly reduced FTH1 transcription in oligodendrocytes, astrocytes and microglia (54,55). These abnormalities are associated with, and may potentially contribute to, the formation of Lewy bodies, where both iron and ferritin are co-deposited (41). However, a direct causal link remains to be established.

The spatiotemporal dynamics of iron distribution are critical in the pathology of PD. The newly developed immunomicroprobe particle-induced X-ray emission technique, which enables the quantification of iron in specific structures such as Lewy bodies at a micron-level resolution, is a powerful tool for elucidating the fine spatiotemporal characteristics of iron metabolism (56). Clinically, CSF profiles from patients with PD experiencing excessive daytime sleepiness reveal a distinct pattern of elevated iron, reduced ferritin and increased IL-1β, suggesting that iron overload may promote excessive daytime sleepiness via microglial activation and neuroinflammation (57).

It is important to note that iron-related mechanisms in PD are context dependent. Although restless leg syndrome (RLS) in the general population is often associated with iron deficiency in the brain, a meta-analysis found no association between PD-RLS and systemic iron parameters, indicating that PD-RLS may involve a pathophysiology distinct from that of the classical iron deficiency hypothesis (58).

ALS, the most common motor neuron disease, is characterized by the progressive degeneration of the upper and lower motor neurons, leading to muscle atrophy, functional impairment and death. Most patients with ALS share the pathological hallmark of the abnormal cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) in motor neurons. As resident immune cells in the brain, microglia exhibit unclear responses to TDP-43 in ALS. Phosphorylated TDP-43 pathology was found to drive the microglial transition from a phagocytically active state, marked by early-stage neuroprotective phagocytic activity via elevated CD68 expression, to a dysfunctional state characterized by late-phase L-ferritin accumulation, thus offering novel insights into ALS pathogenesis (59). Significant spatial and functional associations between microglial activation and abnormal ferritin accumulation underscore their critical roles in ALS progression (60). Given that iron dysmetabolism also occurs during ALS progression, iron is likely to play a pivotal role in ALS pathology. Decreased activity of the AKT signaling pathway may be involved in the dysregulation of iron metabolism in ALS. Specifically, ALS downregulates AKT protein expression and upregulates iron import and storage-related proteins (TfR1, PCBP, FTL and FTH), whereas suppressing the expression of the iron exporter FPN1 may ultimately lead to increased iron accumulation in the skeletal muscle (61). Human spinal cord gene co-expression network analysis identified two key modules enriched for ALS genetic risk: SC.M4 (regulating RNA processing and epigenetics) and SC.M2 (enriched for oligodendrocyte-specific intracellular transport and autophagy-related genes) (62). Within the SC.M2 module, NCOA4 emerged as a computationally inferred hub gene based on co-expression and genome-wide association study data. This position identifies NCOA4 as a statistical risk association for ALS (58), implicating iron dysmetabolism and autophagic imbalance as potential contributors to neurodegeneration.

ACP is a rare autosomal recessive disorder caused by mutations in the ceruloplasmin gene that lead to reduced ferroxidase activity. Patients with ACP typically exhibit a triad of clinical manifestations, including neurological symptoms (cognitive decline, neuropsychiatric abnormalities and movement disorders), retinal degeneration and diabetes mellitus (63). In ACP, Fe³⁺ can be transported to plasma Tf and delivered to other cells. The impaired ferroxidase function of ceruloplasmin in ACP disrupts the conversion of Fe²⁺ to Fe³⁺, thereby inhibiting iron release from the storage sites and reducing systemic iron bioavailability. To meet the iron demands for neurotransmitter synthesis, neurons excessively uptake non-Tf-bound iron, a highly toxic, free iron species that exacerbates neuronal death. FTH, which possesses intrinsic ferroxidase activity, is upregulated in ceruloplasmin-knockout mouse models. This mouse-specific finding suggests a potential compensatory role in maintaining iron homeostasis following ceruloplasmin deficiency (64). Whether FTH is similarly upregulated in patients with ACP remains to be confirmed. Iron-related neurodegeneration in ACP is primarily linked to the abnormal accumulation of magnetic Fe³⁺ within ferritin/hemosiderin cores, predominantly in the form of ferrihydrite-iron, which serves as the principal driver of iron-sensitive MRI contrast (65). Given the rarity of this condition, case reports and individual case analyses remain important resources for investigating its clinical features, genetic mechanisms and therapeutic strategies (63,66).

Friedreich ataxia (FA) is a rare inherited neurodegenerative disorder caused by mutations in the frataxin gene, leading to reduced frataxin protein levels. The most common mutation is a homozygous GAA trinucleotide repeat expansion in the first intron of the frataxin gene. Frataxin is a mitochondrial protein that is essential for mitochondrial function, and its deficiency results in mitochondrial dysfunction, iron accumulation and OS. The degeneration of large sensory neurons in the dorsal root ganglia is an early event in FA; however, the mechanism underlying their heightened vulnerability to frataxin deficiency remains unclear. Reduced ferritin levels (particularly FTH1) are critical for frataxin deficiency-induced ferroptosis, which exacerbates free iron toxicity and oxidative damage to drive neuronal death (67). Targeting ferritin expression or function, such as by enhancing FTH1 activity, may represent a potential therapeutic strategy for FA. In patients with FA, pathological damage to the dentate nucleus is characterized by the progressive atrophy of large neurons. Abnormal iron and ferritin accumulation in white matter oligodendrocytes may represent secondary pathological changes following neuronal atrophy (68). Patients with FA exhibit systemic iron storage depletion and intracellular alterations resembling iron starvation responses, indicating that iron dysregulation in FA reflects an intercompartmental iron redistribution imbalance rather than an absolute overload (69).

Hereditary ferritinopathy, a subtype of neurodegeneration with brain iron accumulation (NBIA), is primarily caused by frameshift mutations in the FTL gene. Its pathology involves the age-dependent amplification of cerebral iron/ferritin deposition. The core mechanism may not involve iron-mediated OS but rather aggregation of mutant FTL, ubiquitination and proteostasis imbalance, triggering cell death, a pathway shared with multiple neurodegenerative diseases (70).

TDP-43 pathological inclusions are hallmark features of limbic-predominant age-related TDP-43 encephalopathy neuropathological changes. Phosphorylated TDP-43 inclusions localized on the surface or interior of small blood vessels are termed Lin bodies. Shahidehpour et al (71) observed frequent co-localization of Lin bodies with ferritin, suggesting that post-hemorrhagic erythrophagocytosis elevates intracellular iron and iron storage proteins, including ferritin.

Progressive supranuclear palsy (PSP), a rare neurodegenerative disease, is characterized by the abnormal aggregation of 4-repeat tau and pathological tau structures (e.g., NFT, globular tangles). In patients with PSP, mitochondrial ferritin accumulates abnormally within substantia nigra neurons. Light chain 3 (LC3), an autophagosome marker, reflects the mitophagy status. The colocalization of LC3 with mitochondrial ferritin in the substantia nigra neurons of patients with PSP supports a model wherein the accumulation of mitochondrial ferritin initially exerts protective effects by chelating iron and reducing ROS levels (72). However, under sustained stress, this protective mechanism fails, leading to accumulated mitochondrial damage, enhanced mitophagy (marked by LC3 accumulation) and cell death (72).

Multiple sclerosis (MS) is a CNS autoimmune disease characterized by inflammatory demyelination and secondary neurodegeneration. Oligodendrocytes in the CNS produce myelin sheaths to wrap axons, enabling rapid saltatory conduction of nerve impulses and maintaining axonal structural integrity. A study using experimental autoimmune encephalomyelitis mice revealed that ferritinophagy controls the generation of lipid ROS via the Fenton reaction, inducing oligodendrocyte death and demyelination at the peak stage of the disease (73).

Multiple system atrophy (MSA), a rare neurodegenerative synucleinopathy, features α-Syn-positive cytoplasmic inclusions in oligodendrocytes, central to neurodegeneration. In an aged proteolipid protein-α-Syn mouse model, which overexpresses α-Syn in oligodendrocytes, iron accumulation and disrupted iron-ferritin interactions were observed in the substantia nigra, putamen and cerebellum (74). Iron elevation in MSA mice may involve ceruloplasmin dysfunction; therefore, targeting iron metabolism represents a potential therapeutic strategy (74).

Wilson's disease, also known as hepatolenticular degeneration, is a rare autosomal recessive disorder caused by ATPase copper transporting β mutations (13q14) that impair copper transport and cause copper accumulation in the liver, brain and kidneys. Of note, patients with Wilson's disease exhibit both copper and iron dysregulation. Elevated ferritin levels in Wilson's disease, which are partially reversible with copper chelation therapy, suggest that iron metabolism disturbances are linked to inflammation and copper toxicity, which require multidimensional interventions (75).

Ferroptosis, an iron-dependent, lipid peroxidation-driven form of cell death, has pathological significance extending beyond single diseases and is emerging as a core mechanism in diverse tissue injuries and chronic disorders. Understanding ferroptosis mechanisms in other diseases will facilitate the precise elucidation of its specificity in neurodegenerative pathologies.

With the global surge in the prevalence of type 2 diabetes (T2D), the associated cognitive dysfunction has become a research focus in neurometabolism, owing to its substantial impact on the quality of life of patients and as a public health burden. Elevated TfR levels alongside decreased ferritin, GPX4 and SLC7A11 levels in the hippocampal neurons of T2D model mice confirm that hippocampal neuronal ferroptosis activation is a crucial mechanism for cognitive impairment (76).

Iron accumulation and ROS synergistically induce neuronal dysfunction, which may constitute a critical mechanism of epileptogenesis. A previous study revealed that, compared with postmortem controls, ferritin expression in epileptic brains exhibited a significant relocation from microglia and oligodendrocytes to astrocytes (77). This finding suggests that strategies to reduce astrocytic iron uptake (thereby attenuating pro-inflammatory responses) may represent a novel therapeutic strategy for treating epilepsy (77).

Neurodegenerative diseases share common pathways in iron dyshomeostasis, yet exhibit distinct, disease-specific manifestations. The common core lies in pathological iron accumulation within specific brain regions, which, through mechanisms such as OS and ferritinophagy, ultimately converges on ferroptosis, a shared cell death pathway. However, key features differ markedly among diseases: Regarding interacting pathological proteins, disrupted iron metabolism forms a vicious cycle with disease-specific protein aggregates: Aβ/tau in AD, α-Syn in PD and TDP-43 in ALS. In terms of predominantly affected cell types, ferritin responses in microglia are particularly prominent in AD and ALS, whereas oligodendrocyte dysfunction plays a more critical role in demyelinating disorders such as MS. In summary, ferritin-mediated iron dysregulation represents a shared pathological nexus in neurodegeneration, yet it is modulated by disease-specific molecular and cellular contexts. This understanding holds significant implications for developing broad-spectrum neuroprotective strategies and precision therapies targeted to specific diseases.

AD is an irreversible neurodegenerative disorder characterized by chronic progressive dementia. Most patients with AD are diagnosed at advanced stages, and no effective therapies currently exist to halt or reverse its progression. Notably, AD has a prolonged preclinical phase before symptom onset; however, current diagnosis primarily relies on clinical observation, which underscores the urgent need for the early identification of specific biomarkers to enable precise diagnosis and intervention. AD is associated with chronic inflammation, OS, mitochondrial dysfunction and neurotoxicity. Studies have suggested that disrupted iron homeostasis may be another potential pathogenic factor in AD. Cerebral iron deposition exacerbates oxidative damage through the Fenton reaction, directly contributing to AD pathological processes. Iron homeostasis-associated proteins (e.g., ferritin, Tf), which are responsible for iron storage and transport, may reflect early-stage metabolic disturbances in AD through changes in their expression levels. Consequently, iron and iron-related proteins have emerged as potential biomarker candidates. However, its role in AD remains elusive.

CSF ferritin, a biomarker implicated in iron metabolism regulation and inflammatory responses, shows significant potential for the early detection of AD. CSF ferritin levels are significantly elevated during the preclinical stages of AD and correlate with complement activation and other inflammatory markers, suggesting its role as a key bridging molecule that links neuroinflammation and neurodegeneration (78,79). A recent systematic review and meta-analysis, encompassing 25 studies and 3,469 participants, confirmed that CSF ferritin levels are significantly elevated in patients with AD compared to controls (pooled standardized mean difference=0.44, 95% CI: 0.02-0.86) (80). This population-level evidence strengthens the case for ferritin as a quantifiable biomarker linked to AD pathology.

Regarding classic AD pathology, ferritin shows a particularly strong association with tau pathology. A positive correlation between CSF ferritin and p-tau levels was revealed and it was mediated by ApoE (49). Furthermore, regardless of the cerebral Aβ deposition status, CSF ferritin levels are consistently elevated in subjects with high total tau and correlate with other neuronal injury markers such as fatty acid-binding protein 3, collectively pointing to a tau-driven neurodegenerative pathway (38,81). However, CSF ferritin levels are not significantly associated with cerebral amyloid pathology (38). Taken together, these findings position CSF ferritin primarily as a marker related to tau pathology and consequent neurodegeneration, rather than a general marker of AD. This characteristic supports its utility in differential diagnosis. For instance, in cerebral amyloid angiopathy, which also features Aβ deposition, CSF ferritin correlates negatively with both Aβ-40 and Aβ-42 levels, a pattern distinct from that observed in AD, potentially aiding in distinguishing these frequently co-occurring disorders (82). It should be noted, however, that these findings are based on limited data and small sample sizes, necessitating further validation.

Serum ferritin levels in peripheral blood are also clinically relevant. Serum ferritin levels positively correlate with AD severity, and its combination with homocysteine and C-reactive protein significantly improves the diagnostic efficacy for AD with mild cognitive impairment (83). However, a longitudinal analysis of multiorgan blood parameters reported a negative correlation between plasma ferritin levels and AD severity, suggesting that its dynamic changes may be more complex and potentially useful as a marker of disease progression (84). Beyond AD-specific pathology, systemic factors such as chronic heart failure have been found to influence phosphorylated tau, possibly through the modulation of serum ferritin levels, revealing a potential interaction between systemic circulation and CNS pathology (85).

Finally, individual differences, including genotype and long-term dietary habits, significantly modulated the expression of AD biomarkers in the hippocampus (47). This adds a layer of complexity to the clinical application of ferritin and other biomarkers, emphasizing the necessity for a comprehensive perspective in future research and clinical interpretation that situates biomarkers within an individual's overall physiological and pathological contexts.

Iron is essential for ROS generation, which induces OS and subsequent damage to neurons in the substantia nigra of patients with PD. Various techniques have been developed to assess iron and related biomarker concentrations. Biochemical analyses, histopathological studies and neuroimaging have demonstrated that iron deposition in patients with PD is primarily localized to the substantia nigra. However, investigations on iron levels across diverse biological fluids from patients with PD have yielded conflicting results regarding both the direction of change (increase, decrease or no difference) and their correlation with clinical features (86-88).

Emerging evidence suggests that ferritin levels are associated with disease progression and specific clinical manifestations of PD. In the CSF, a longitudinal study revealed a significant increase in total iron and a decrease in ferritin levels over time, indicating its potential as a dynamic marker of disease progression (87). Furthermore, elevated CSF ferritin levels negatively correlate with Mini-Mental State Examination scores in patients with PD dementia, supporting the detrimental role of cerebral iron accumulation in cognitive function (89). Furthermore, altered serum ferritin levels have been observed in patients with PD compared with healthy controls (90). Serum ferritin levels have also been positively correlated with the volumes of key brain structures, including the caudate nucleus and putamen, suggesting that serum ferritin levels may serve as a biomarker reflecting disease burden or the extent of neurodegeneration in PD (88). However, it is important to note that peripheral ferritin levels may not directly correlate with brain iron content as measured by specialized MRI techniques, and thus, their interpretation requires caution. Combining it with neuroimaging features could enhance this assessment.

The establishment of ferritin as a reliable biomarker faces significant challenges. First, study findings have been inconsistent. Some reports have found no significant differences in serum ferritin or Tf levels between patients and controls (91). A systematic meta-analysis further highlighted that although neuroimaging techniques consistently show increased iron concentrations in the substantia nigra, serum and CSF iron-related parameters lack consistent changes (92). Second, ferritin lacks specificity, as plasma levels have been proven ineffective in predicting PD risk in individuals carrying pathogenic mutations in the gene encoding the enzyme β-glucocerebrosidase (93). More importantly, the correlation between peripheral iron indices and iron accumulation in the brain remains elusive. No significant association between subcortical iron and blood iron markers has been reported, suggesting that cerebral iron accumulation in neurodegeneration may be independent of systemic iron status and potentially regulated by local inflammatory processes (94).

Altogether, the value of ferritin as a biomarker is primarily related to disease progression and certain clinical symptoms. However, its specificity, sensitivity and complex relationship with the peripheral iron status are major obstacles. A Mendelian randomization study offered a new perspective, revealing a genetic causal link between lower serum iron levels (but not ferritin, total iron-binding capacity or Tf saturation) and increased PD risk (95). This Mendelian randomization study specifically links genetically lowered serum iron to PD risk. The absence of a link for ferritin in this analysis likely means that the genetic variants used are not strong drivers of ferritin levels; however, ferritin is not biologically unimportant in PD. This underscores the need to precisely define the roles of different iron metabolism parameters in future studies. Overall, ferritin is more likely to serve as a component of a multimodal biomarker panel than as a standalone diagnostic tool.

Emerging evidence highlights the critical role of ferritin as a biomarker of neurodegenerative disorders. Although dysregulated iron metabolism in PD is closely linked to nigral neurodegeneration and cognitive decline, similar iron homeostasis imbalances, marked by elevated serum ferritin levels, have been implicated in the pathophysiology of ALS, reflecting the shared yet distinct mechanisms of OS and neuroinflammation. A large-scale, multicenter, longitudinal, multimodal body fluid biomarker cohort study systematically evaluated the utility of multiple candidate biomarkers for ALS stratification and potential therapeutic evaluation, and demonstrated significantly elevated serum ferritin levels in patients with ALS (96). A systematic review and meta-analysis confirmed elevated serum ferritin levels in patients with ALS, and serum ferritin levels negatively correlated with survival (hazard ratio=1.38; 95% CI, 1.02-1.88; P=0.039) (97). These findings provide new evidence for the involvement of energy metabolism dysregulation, OS-mediated iron homeostasis imbalance and immune dysregulation in ALS pathophysiology.

Although ferritin levels in CSF and blood are altered (increased or decreased) in AD, PD and ALS, its use as an independent diagnostic biomarker with high sensitivity and specificity faces significant challenges. Most existing studies report associations but lack large-scale validation with unified, well-defined diagnostic cutoff values. Furthermore, the majority of research uses clinical diagnosis rather than more precise gold standards, such as amyloid-β positron emission tomography (Aβ-PET), tau-PET or neuropathology, as the reference, which introduces bias when evaluating diagnostic performance. Thus, the core clinical value of ferritin may not lie in replacing established core diagnostic markers, but rather in serving a complementary role. The most promising direction lies in combining ferritin with neurofilament light chain, neuroimaging measures and other inflammatory indicators to construct multimodal diagnostic models.