Microglial iron accumulation serves as a key trigger for ferroptosis, which in turn amplifies neuroinflammation through the release of pro-inflammatory cytokines (Liu S. et al., 2022). Notably, among central nervous system cells, microglia demonstrate a particularly high susceptibility to ferroptosis compared to neurons and astrocytes. This vulnerability may compromise their ability to clear pathological α-syn aggregates via phagocytosis. Supporting this, removal of microglia from tri-culture systems significantly delayed the rate and extent of iron-induced neuronal death, underscoring the essential role of microglia in mediating ferroptotic neurotoxicity (Ryan et al., 2023). Further evidence from non-human primate models shows that intranasal administration of α-syn preformed fibrils leads to iron deposition specifically within microglia, rather than DA neurons, in the substantia nigra. This suggests that microglial iron accumulation may represent an early event triggering neuroinflammation prior to neuronal degeneration in PD (Guo et al., 2021). Thus, microglia are not only highly vulnerable to ferroptosis but also act as crucial mediators of iron-dependent neurotoxicity in PD.

Changes in the central nervous microenvironment significantly influence microglial polarization. Classically activated M1 microglia, induced by stimuli such as lipopolysaccharide (LPS) and interferon-gamma (IFN-γ), release neurotoxic cytokines including IL-1β and tumor necrosis factor alpha (TNF-α). In contrast, alternatively activated M2 microglia, polarized by IL-4 or IL-13, secrete protective factors like TGF-β and IL-10 that promote tissue repair and homeostasis. The dynamic balance between these phenotypes is essential for regulating neuroinflammation (Zhao et al., 2026). Importantly, iron accumulation within microglia drives them toward a pro-inflammatory M1 state, which not only exacerbates neuroinflammation and DA neuronal loss but also establishes a vicious cycle involving inflammasome activation and ferroptosis (Yu et al., 2023). Therapeutic modulation of this balance is emerging: for example, overexpression of Angiotensin-Converting Enzyme-2 (ACE2) shifts microglia toward the protective M2 phenotype, reducing dopaminergic neurodegeneration. Mechanistically, ACE2 upregulates osteoprotegerin (OPG), thereby inhibiting the non-canonical NF-κB pathway mediated by RANKL (Xu Y. et al., 2025). These findings highlight the critical role of iron in driving microglial polarization toward a pro-inflammatory state and identify phenotype switching as a viable therapeutic target.

Novel molecular regulators of microglial ferroptosis are continually being identified. A genome-wide CRISPR screen revealed that SEC24B, a gene involved in vesicle trafficking, plays a critical role in regulating ferroptosis in microglia. Its knockout markedly reduced lipid peroxidation and suppressed ferroptosis (Ryan et al., 2023). Additionally, studies in rotenone-induced PD models demonstrated that microglial complement receptor 3 (CR3) activates NADPH oxidase 2 (NOX2), leading to ROS production. This microglia-derived ROS induces neuronal iron deposition and lipid peroxidation, ultimately promoting DA neuron ferroptosis (Wang et al., 2024). Subsequent research confirmed that gp91phox, a key subunit of NOX2, promotes microglial activation, neuroinflammation, and ferroptosis, contributing to cognitive deficits in PD mice—suggesting that targeting gp91phox may offer a promising therapeutic strategy (Tian et al., 2024). These discoveries emphasize the importance of intracellular trafficking and ROS generation in microglial ferroptosis and neuroinflammation.

Mutations in Leucine-rich repeat kinase 2 (LRRK2), one of the most common genetic causes of familial PD, impair lysosomal degradation within microglia (Zhao et al., 2026). These mutations disrupt iron homeostasis by phosphorylating Rab8a, leading to the sequestration of Tf within lysosomes and potentially promoting iron accumulation and ferroptosis. Stimulation with α-syn upregulates LRRK2, which suppresses the protective p62-Keap1-Nrf2 pathway. This suppression results in microglial ferroptosis, release of pro-inflammatory cytokines, and subsequent DA neuron loss. Inhibiting LRRK2 activated this pathway, attenuated ferroptosis, reduced neuroinflammation, and improved motor deficits (Liu et al., 2025). Thus, LRRK2 promotes microglial activation by modulating ferroptosis and NF-κB signaling. The System Xc⁻–GSH–GPX4 antioxidant axis plays a central role in mediating LRRK2-dependent microglial ferroptosis and inflammation (Zheng et al., 2024). Overall, these studies establish LRRK2 as a key regulator of microglial iron metabolism and inflammatory responses through ferroptosis-dependent mechanisms.

DJ-1 acts as an endogenous inhibitor of ferroptosis, in part by maintaining cysteine synthesis via the transsulfuration pathway (Cao et al., 2020). Specifically, DJ-1 preserves the activity of S-adenosylhomocysteine hydrolase (SAHH), the key enzyme that hydrolyzes S-adenosylhomocysteine (SAH) to homocysteine within this metabolic cascade. Mechanistically, DJ-1 prevents the enhanced inhibitory interaction between SAHH and its negative regulator S-adenosylhomocysteine hydrolase-like 1 protein (AHCYL1), thereby promoting the formation of catalytically active SAHH tetramers. This ensures sustained homocysteine flux, which is critically converted to cysteine for GSH biosynthesis when the canonical cystine/glutamate antiporter (system xc-) is inhibited, a common trigger for ferroptosis (Cao et al., 2020). By safeguarding this metabolic bypass, DJ-1 directly supports the cellular antioxidant capacity to counteract lethal lipid peroxidation, a defining hallmark of ferroptosis.

Although the functions of DJ-1 are diverse, its role in microglia remains relatively underexplored (Dolgacheva et al., 2019). DJ-1 deficiency increases the sensitivity of microglia to dopamine, elevating monoamine oxidase (MAO) activity while reducing TREM2 expression. This trigger increased ROS production and pro-inflammatory cytokine release, ultimately exacerbating neurotoxicity (Trudler et al., 2014). Moreover, loss of DJ-1 impairs microglial function through heightened inflammatory response to α-syn, reduced α-syn uptake due to lipid raft disruption, and defective autophagy-lysosomal degradation (Nash et al., 2017). These dysfunctions collectively suggest that DJ-1 deficiency in microglia contributes to PD pathogenesis not only through enhanced neuroinflammation and oxidative stress but also potentially by compromising the intrinsic ferroptosis defense mechanism. The loss of DJ-1-mediated maintenance of the transsulfuration pathway could render microglia more vulnerable to ferroptotic damage, thereby linking its classical cytoprotective role in redox homeostasis directly to the emerging pathway of ferroptosis in neurodegeneration.

In summary, microglia play a central role in PD progression by linking iron dyshomeostasis, neuroinflammation, and ferroptosis. Key mechanisms include their high susceptibility to iron-dependent cell death, polarization toward a pro-inflammatory state under iron overload, and genetic regulation by factors such as LRRK2 and DJ-1. Targeting microglial ferroptosis and phenotype switching represents a promising therapeutic strategy to disrupt neuroinflammatory cycles and mitigate neurodegeneration in PD.

Astrocytes play a vital role in supporting and protecting the healthy nervous system through the release of neurotrophic factors, production of antioxidants, and clearance of neuronal waste. Under pathological conditions such as PD, astrocyte function becomes profoundly altered, significantly influencing neuronal susceptibility to ferroptosis.

Astrocytes contribute to neuronal ferroptosis through a disrupted fibroblast growth factor (FGF) signaling pathway with oligodendrocytes. Impaired FGF1/FGF9-FGFR interactions, heightened mitochondrial oxidative phosphorylation, and Ca²⁺ influx lead to excessive ROS production, ultimately promoting iron accumulation and DA neuron death in the SN (Zhang S. et al., 2025). The concept of neuroprotective (A2-type) and neurotoxic (A1-type) reactive astrocytes reflects dynamic transitional states within a continuum of the same astrocyte lineage, rather than fixed subtypes. Resting astrocytes exposed to inflammatory stimuli initially adopt a transient neuroprotective state before transitioning into a sustained neurotoxic state. This phenotypic shift is primarily regulated by the mTOR signaling pathway. In PD mouse models, reducing mTOR activity or expression levels in astrocytes diminishes their neurotoxicity and alleviates neurodegenerative phenotypes. Importantly, mTOR inhibition (e.g., via rapamycin) helps maintain astrocytes in a protective state and reduces neuronal lipid peroxidation damage (Zhang et al., 2025c). This understanding of the continuous evolution of astrocyte states offers time-sensitive therapeutic opportunities for neurodegenerative diseases. Additionally, recent research shows that cystathionine γ-lyase (CSE) drives astrocytes toward a neurotoxic phenotype in PD by forming a complex with Yes-associated protein (YAP), which activates Forkhead box D3(FOXD3)-mediated transcription of neuroinflammation-related genes (Zhu et al., 2024).

Reactive astrocytes counteract oxidative stress by activating nuclear factor erythroid-2-related factor 2 (Nrf2) and releasing various antioxidant molecules, such asGSH and metallothioneins (MTs). Nrf2 regulates the expression of antioxidant enzymes by binding to antioxidant response elements (AREs) and is essential for maintaining GSH homeostasis (Ovesen et al., 2014). Crucially, astrocytes employ the Nrf2/ARE pathway to suppress ferroptosis and protect DA neurons in PD models (Chen et al., 2009). Gene therapy strategies that activate the Nrf2/ARE pathway in astrocytes have been shown to reduce oxidative stress and provide neuroprotection to DA neurons in both in vitro and in vivo settings (Williamson et al., 2012). However, this protective mechanism can be impaired; disrupted crosstalk between oligodendrocytes and astrocytes, mediated by the FGF signaling pathway, weakens astrocytic defense capacity. GSH, the most abundant antioxidant in the CNS, is synthesized in astrocytes following cystine uptake (Asanuma and Miyazaki, 2021). In addition to GSH, astrocytes produce MTs, potent antioxidants that are overexpressed in the PD brain (Michael et al., 2011). Furthermore, reduced expression of melatonin receptor 1A (MT1) in astrocytes leads to increased pathological Ca²⁺ influx, exacerbating oxidative stress and suppressing the NRF2/SLC7A11/GPX4 antioxidant axis, ultimately promoting neuronal ferroptosis (Zhang S. et al., 2025).

Astrocytes are the primary producers of apolipoproteins (ApoA1, D, E, J) in the CNS, which help maintain neuronal homeostasis through lipid transport, antioxidant activity, and anti-apoptotic functions. ApoA1 promotes reverse cholesterol transport via the ABCA1 transporter, although its overexpression may paradoxically worsen neuroinflammation. ApoD directly counteracts neuronal ferroptosis by sustaining GSH levels and inhibiting lipid peroxidation. The elevated ApoD levels observed in the CSF of PD patients may represent a compensatory protective response. ApoE isoforms (except E4) suppress ferroptosis by activating the PI3K/AKT pathway, thereby inhibiting ferritinophagy and pathological iron release. ApoJ (Clusterin) indirectly inhibits ferroptosis by binding α-syn oligomers, suppressing their spread and reducing associated oxidative stress. In contrast, the ApoE4 isoform has detrimental effects: its unstable lipoprotein particles exacerbate neuronal lipid peroxidation and ferroptosis, significantly correlating with increased PD risk (Dai et al., 2025).

Conversely, harmful pathways are also activated. Upregulation of NOX4 in hippocampal astrocytes during PD promotes neuroinflammation and mitochondrial damage by increasing myeloperoxidase (MPO) and osteopontin (OPN). This cascade induces ferroptosis through elevated oxidative stress and impairment of the mitochondrial electron transport chain (Boonpraman et al., 2023). Notably, astrocytes also exhibit protective intercellular communication mechanisms; for instance, ferritin released by astrocytes can be taken up by neighbori ng MES23.5 DA neurons in co-culture systems. This ferritin transfer significantly alleviates MPP⁺(the active neurotoxic metabolite of MPTP)-induced damage and inhibits ferroptosis in DA neurons (Zhang et al., 2022).

DJ-1, which is predominantly expressed in human astrocytes, exerts multiple neuroprotective effects by regulating oxidative stress, maintaining mitochondrial function, and modulating anti-inflammatory responses (Miyazaki and Asanuma, 2020). Accordingly, DJ-1 knockout has been shown to impair astrocyte-mediated protection against 6-hydroxydopamine toxicity (Lev et al., 2013). Furthermore, loss of DJ-1 in astrocytes leads to hyperactivation of inflammatory responses upon LPS stimulation, resulting in excessive production of nitric oxide (NO), COX-2, and IL-6 via a ROS-p38 MAPK pathway (Waak et al., 2009). This dysregulation may contribute to PD pathogenesis by promoting nitrative stress.

Beyond these well-characterized roles, emerging evidence positions DJ-1 as a critical guardian against ferroptosis, a function highly relevant to astrocyte-mediated neuroprotection. The molecular mechanism, elucidated in cancer cells but likely conserved in neural cells, involves DJ-1 sustaining the transsulfuration pathway (Cao et al., 2020). As detailed in Section 2.1, DJ-1 maintains the activity of SAHH, ensuring the production of homocysteine and subsequently cysteine for GSH synthesis. In astrocytes, this function may be crucial for maintaining their own robust antioxidant reservoir, enabling them to effectively buffer neuronal oxidative stress and neutralize lipid peroxides. Furthermore, by securing their metabolic resilience against ferroptosis, DJ-1-competent astrocytes can better provide trophic support, regulate extracellular glutamate, and mitigate neuroinflammatory cascades, all processes that indirectly influence neuronal susceptibility to ferroptotic death (Cao et al., 2020).

Conversely, DJ-1 overexpression preserves astrocyte function and prevents oxidative stress. Astrocytic DJ-1 overexpression provides neuroprotection against MPP⁺-induced DA neuron loss and motor deficits. Proteomic analyses indicate that DJ-1 activates the Nrf2 pathway, modulating antioxidant responses and metabolic enzymes to counteract oxidative stress in transgenic zebrafish (Frøyset et al., 2018). This Nrf2 activation may work in concert with the SAHH-dependent maintenance of the transsulfuration pathway, creating a multi-layered defense system wherein DJ-1 coordinately enhances both the synthesis (via transsulfuration) and the utilization (via Nrf2-target genes like GCLM) of glutathione. These findings collectively highlight the multifaceted neuroprotective influence of astrocytic DJ-1 on DA neurons, extending from classical anti-inflammatory and antioxidant support to include the preservation of a key metabolic pathway that directly counters the execution of ferroptosis.

Astrocytes play a dual role in PD, acting both as protectors and contributors to neurodegeneration through mechanisms involving ferroptosis, oxidative stress, and neuroinflammation. Their ability to transition between neurotoxic and neuroprotective states highlights their dynamic influence on disease progression. Key pathways such as mTOR, Nrf2, and DJ-1 signaling offer promising targets for therapeutic intervention. Enhancing astrocyte-mediated defense mechanisms while suppressing harmful responses could pave the way for novel strategies to halt or slow neuronal loss in PD. Understanding the complex roles of astrocytes provides not only deeper insights into PD pathogenesis but also opportunities for developing astrocyte-centered therapies.

Beyond microglia and astrocytes, the pathogenic milieu of PD involves several other cellular players. Oligodendrocytes, the myelinating cells of the CNS, can release excess iron under pathological conditions such as demyelination, thereby contributing to neuronal iron overload and ferroptosis. Notably, alterations in oligodendrocyte gene expression emerge early in PD, even before overt dopaminergic degeneration, pointing to their role in initial disease mechanisms. While dysfunctional oligodendrocytes may exacerbate neurodegeneration, they also exert protective effects, such as secreting the iron-storage protein FTH1 to counter iron-mediated cytotoxicity (Li M. et al., 2024). In addition, peripheral immune cells, including T-cells and monocytes, infiltrate the CNS in PD and modulate neuroinflammation. Their crosstalk with resident glia amplifies inflammatory responses and influences disease progression (Brodacki et al., 2008; Brochard et al., 2009). The blood–brain barrier (BBB) endothelial cells also play a critical role: they regulate the bidirectional transport of pathological proteins like α-synuclein, and their dysfunction impairs protein clearance while promoting aggregation, thereby accelerating PD pathology. Moreover, activated BBB endothelial cells exacerbate neuroinflammation by releasing cytokines and facilitating leukocyte infiltration into the brain, further amplifying neurodegeneration (Yuan et al., 2023). Thus, a comprehensive understanding of PD pathogenesis requires integrating this multicellular network, in which neuronal vulnerability is shaped by dysregulated interactions among neurons, glia, vascular cells, and peripheral immune components.

Several therapeutic strategies are currently focused on directly inhibiting the aggregation of α-syn. Among these, small molecules and antibodies designed to target the P1–P2 region of α-syn oligomers or fibrils aim to selectively suppress pathological aggregation. For instance, αSP1, a synthetic antibody (sybody) binding the P1 region (residues 36–42) of α-syn, effectively inhibits amyloid aggregation at low stoichiometries by engaging both oligomeric and fibrillar species. It disrupts primary and secondary nucleation processes, reduces cytotoxicity, and maintains specificity within complex biological environments, highlighting its potential as a therapeutic strategy for synucleinopathies such as PD (Gialama et al., 2024). In contrast, prasinezumab, a monoclonal antibody targeting aggregated α-syn, was evaluated in the phase 2 PASADENA trial (NCT03100149). Despite doses of 1,500 mg or 4,500 mg, no significant differences were observed compared to placebo in reducing MDS-UPDRS total scores (Parts I–III) at 52 weeks. Furthermore, the treatment showed no meaningful effects on dopamine transporter imaging or clinical progression, although infusion-related reactions were reported in 19–34% of participants. These results suggest a lack of disease-modifying effects in early-stage PD patients (Pagano et al., 2022). An ongoing phase 2b trial, PADOVA (NCT04777331), is now evaluating prasinezumab in an older cohort with longer disease duration and more severe motor symptoms. Outcomes are currently pending (Nikolcheva et al., 2025).

Another approach involves structure-based inhibitors that prevent α-syn misfolding and oligomerization, thereby reducing susceptibility to ferroptosis. The peptide inhibitor 4,554 W, derived from the preNAC region (residues 45–54) of α-syn and stabilized by N-acetylation and C-amidation, incorporates into β-sheet structures and interferes with fibril nucleation. In transgenic models, it reduced fibril formation by 62% and striatal deposits by 41%, while also improving motor function without eliciting significant immunogenicity. However, its clinical translation is hampered by poor blood–brain barrier penetration (Meade et al., 2020). Beyond peptide-based agents, small molecules such as SynuClean-D (SC-D) exhibit broad efficacy against various α-syn amyloid strains. SC-D inhibits aggregation, prevents seeded polymerization, and disaggregates preformed fibrils. It also reduces intracellular accumulation of phosphorylated α-syn inclusions in a strain-dependent manner. Although SC-D currently lacks optimal drug-like properties, it represents a valuable tool for proof-of-concept studies and high-throughput screening (Peña-Díaz et al., 2022).

Active immunotherapy has also been explored, as demonstrated by PD01A, which showed favorable tolerability in early PD patients over six immunizations administered across five years. Robust antibody responses with geometric mean titers reaching 1:20,218 confirmed target engagement. Booster immunizations effectively reactivated humoral immunity, supporting progression to phase 2 trials (Volc et al., 2020). Collectively, these findings reflect sustained interest in immunotherapeutic and aggregation-inhibiting strategies, despite mixed outcomes in clinical trials to date.

Emerging evidence highlights the interplay between α-syn aggregation and ferroptosis in PD, revealing multi-target therapeutic opportunities. Pyridoxal phosphate (PLP), the active coenzyme form of vitamin B6, activates GOT1 to enhance the methionine salvage pathway and increase GSH synthesis. This action suppresses α-synuclein-induced ferroptosis and protects DA neurons, highlighting its potential for repurposing in PD therapy (Min et al., 2025). Similarly, melatonin receptor MT1 deficiency exacerbates α-syn pathology and ferroptosis in PD models by disrupting the Sirt1/Nrf2/HO-1/GPX4 axis and promoting iron accumulation, whereas MT1 overexpression attenuates these effects (Lv et al., 2024). Natural products also demonstrate promise: the fungal-derived meroterpenoid granulathiazole A (GA) activates Nrf2/HO-1 signaling, inhibits ferroptosis via SLC7A11/GPX4/FSP1 upregulation and ACSL4 downregulation, and reduces α-syn accumulation across cellular and zebrafish models (Li et al., 2024a). Likewise, acteoside, a plant-derived compound, counteracts neuronal damage through PI3K/Akt-mediated Nrf2 activation, restoring redox balance and inhibiting ferroptosis (Wang et al., 2025). Together, these findings underscore the therapeutic potential of simultaneously targeting α-syn aggregation and ferroptosis pathways.

Deferiprone (DFP), an FDA-approved oral iron chelator capable of crossing the blood–brain barrier, reduces nigral iron content, suppresses α-syn aggregation, and protects DA neurons through dual inhibition of iron-dependent α-syn fibrillation and ferroptosis. In MPTP-induced PD mice, DFP significantly reduced iron deposition in the substantia nigra, increased DA neuron survival, and improved motor function (Zeng et al., 2021). However, clinical outcomes have been mixed: a phase II randomized controlled trial (RCT) in early-onset PD patients showed that short-term DFP treatment was safe but only trended toward motor improvement (Martin-Bastida et al., 2017). Another RCT in newly diagnosed PD patients found that DFP accelerated disease progression and necessitated earlier dopaminergic therapy (Devos et al., 2022). These trials indicate that DFP has not achieved desired efficacy and is associated with significant adverse effects, limiting its application in PD.

Dexrazoxane (Dex), a highly hydrophilic iron chelator, binds free iron and enters the brain through a compromised BBB. In PD animal models, intraperitoneal administration of Dex improved contralateral rotation behavior and motor dysfunction by reducing oxidative damage and systemic inflammation (Mei et al., 2019). Similarly, BJP-IVb protects against PD by suppressing iron overload-mediated ferroptosis of DA neurons. It inhibits IRP2, reduces iron transport and lipid peroxidation, and improves motor function (Li et al., 2024b). Although iron chelation remains conceptually appealing, clinical translation requires more targeted and tolerable agents.

The interplay between α-syn aggregation and ferroptosis forms a key pathogenic loop in PD. These therapeutic strategies offer promising avenues to disrupt this cycle. Although several agents have demonstrated compelling efficacy in preclinical studies, clinical outcomes for many candidates remain limited. Future research should prioritize combination therapies, enhance blood–brain barrier penetration, and develop patient stratification strategies based on iron deposition and α-syn pathology. A summary of these therapeutic approaches is provided in Table 2.

Astrocytes, the most abundant glial cells in the central nervous system, play essential roles in supporting neuronal function, regulating antioxidant defense, and maintaining metabolic homeostasis.

Activation of the Nrf2 signaling pathway in astrocytes provides neuroprotection by promoting the production of various antioxidant molecules. This pathway serves as a critical regulator of cellular redox homeostasis, particularly under oxidative stress conditions such as those found in PD. Targeting astrocytic serotonin 1A (5-HT1A) receptors with (R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) stimulates astrocyte proliferation and upregulates metallothionein (MT-1/−2) expression via Nrf2 nuclear translocation. This process reduces DA neuron loss and enhances astrocytic metallothionein levels (Miyazaki et al., 2013).

Additionally, the anti-Parkinson’s drug rotigotine increases striatal astrocytic MT-1/2 and protects nigral DA neurons in a 6-hydroxydopamine (6-OHDA) mouse model of PD through activation of astrocytic 5-HT1A receptors, highlighting its potential as a neuroprotective therapy against dopaminergic degeneration (Isooka et al., 2020). Beyond receptor-specific agents, other agents also exert neuroprotective effects by activating the Nrf2 pathway. For instance, the probiotic strain Lactococcus lactis MG1363-pMG36e-GLP-1 activates the Nrf2/GPX4 signaling pathway to inhibit ferroptosis, ameliorating motor deficits in PD mice (Yue et al., 2022). Moreover, therapeutic compounds such as melatonin, salidroside, and quercetin demonstrate neuroprotective properties in PD models via activation of the Nrf2/GPX4 pathway (Lv et al., 2024; Shen J. et al., 2024; Lin et al., 2022). These findings collectively underscore the broad therapeutic potential of targeting the Nrf2 system within astrocytes to mitigate oxidative damage and ferroptosis in PD.

The system Xc⁻–GPX4 axis represents a central mechanism in the cellular defense against ferroptosis, serving as a critical regulatory node in maintaining redox balance and lipid peroxidation homeostasis. Studies have shown that the antiepileptic drugs levetiracetam (LEV) and zonisamide (ZNS) protect DA neurons from 6-OHDA-induced toxicity by upregulating the xCT transporter in astrocytes, thereby increasing GSH levels (Miyazaki et al., 2016; Asanuma et al., 2010). This underscores the broader relevance of repurposing existing drugs for neuroprotection through astrocyte-mediated mechanisms. Furthermore, activation of the system Xc⁻–GPX4 pathway enhances antioxidant capacity and represents a promising therapeutic strategy. In an MPTP-induced mouse model of PD, oral administration of total flavonoids of Astragalus (TFA) increased GPX4 expression, elevated GSH levels, reduced ROS production, and suppressed neuronal ferroptosis (Gao et al., 2024). Subsequent clinical double-blind controlled trials indicated that multi-dose flavonoid regimens (200–800 mg daily) were safe, well-tolerated, and without significant accumulation, supporting the potential of flavonoid-based supplements in PD management (Pang et al., 2016). These results bridge preclinical findings with clinical applicability, highlighting flavonoids as feasible adjunct therapeutics. GSH, a critical antioxidant, plays a vital role in neuronal protection. N-Acetylcysteine (NAC), a precursor of GSH, helps sustain redox homeostasis and mitigates oxidative damage. Intravenous NAC administration significantly increases dopamine transporter (DAT) binding in the caudate and putamen, correlating with marked clinical improvement (Monti et al., 2019). These findings underscore that astrocytic xCT-GPX4 represents a key target for neuroprotection, offering a novel therapeutic strategy for preventing dopaminergic neurodegeneration.

Astrocytes significantly contribute to the regulation of ferroptosis in PD through mechanisms involving the Nrf2 pathway and system Xc⁻–GPX4 signaling. Therapeutic targeting of astrocytic receptors and antioxidant pathways presents a promising direction for developing neuroprotective treatments aimed at preserving DA neurons and slowing disease progression.