Ferroptosis in major depressive disorder: Molecular mechanisms, cellular vulnerability, and therapeutic opportunities

Deyue Kong; Ruiqi Duan; Xiangyu Wang; Xiaoyuan Wang; Jie Zhao

doi:10.1016/j.bbrep.2026.102798

. 2026 Sep 18;48:102798. doi: 10.1016/j.bbrep.2026.102798

Ferroptosis in major depressive disorder: Molecular mechanisms, cellular vulnerability, and therapeutic opportunities

Deyue Kong ^a,^b, Ruiqi Duan ^a, Xiangyu Wang ^a, Xiaoyuan Wang ^a, Jie Zhao ^b,^c,^⁎

PMCID: PMC13625795 PMID: 42819418

Abstract

Major depressive disorder (MDD) is a heterogeneous psychiatric disorder involving oxidative stress, neuroinflammation, mitochondrial dysfunction, impaired neuroplasticity, and metabolic dysregulation. Ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation and antioxidant defense failure, has recently attracted attention as a potential mechanism linking these pathological processes. This review summarizes the molecular basis of ferroptosis in MDD, focusing on iron dyshomeostasis, lipid peroxidation, and disruption of the System Xc⁻/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis. We further discuss ferroptosis-related alterations in depression-associated models and vulnerable brain regions, with attention to neurons, neural progenitor cells, microglia, astrocytes, and emerging systemic contributors. Importantly, these ferroptosis-related molecular alterations are currently best interpreted as candidate contributors to MDD-associated pathological networks, rather than as an established disease mechanism.

Current evidence suggests that ferroptosis in MDD is unlikely to represent an isolated neuronal death process. Instead, it may function as a stress-responsive and multicellular pathological framework that intersects with neuroinflammation, glutamatergic disturbance, mitochondrial injury, and brain–periphery communication. Therapeutically, natural products, traditional medicine formulas, chemical agents, ferroptosis inhibitors, nutrients, microbial metabolites, and non-pharmacological interventions have shown antidepressant-like effects mainly in preclinical MDD models by modulating ferroptosis-related pathways. These interventions commonly converge on restoration of the System Xc⁻/GSH/GPX4 axis, activation of nuclear factor erythroid 2-related factor 2 (Nrf2)-centered antioxidant signaling, regulation of iron metabolism, suppression of lipid peroxidation, and inhibition of inflammatory pathways. However, current evidence remains largely preclinical, and future studies should strengthen cell-specific validation, causal mechanistic analysis, and clinical translation.

Keywords: Major depressive disorder, Ferroptosis, Oxidative stress, Neuroinflammation, Natural products

Highlights

•
Ferroptosis involves iron dyshomeostasis, lipid peroxidation, and System Xc⁻/GSH/GPX4 dysfunction.
•
Depression-related ferroptosis involves neurons, microglia, astrocytes, and systemic factors.
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Natural products, traditional medicine, and drugs show anti-ferroptotic antidepressant potential in preclinical models.
•
act via antioxidant and anti-inflammatory networks, but clinical relevance remains unclear.

1. Introduction

Major depressive disorder (MDD) is a common psychiatric disorder characterized by persistent low mood, anhedonia, cognitive impairment, sleep disturbances, and other affective and somatic symptoms [1]. Owing to its high prevalence, recurrent nature, and close association with functional impairment and suicide risk, depression has become a major global health concern [2]. Although a range of pharmacological and psychotherapeutic interventions is currently available, many patients still experience delayed onset of therapeutic benefit, incomplete remission, adverse effects, or poor treatment response [3]. These clinical challenges have sustained interest in identifying novel mechanisms and treatment strategies for depression (see Table 1, Table 2, Table 3).

Table 1.

Natural products and traditional medicine-related interventions targeting ferroptosis in depression-related model.

Intervention	Model/context	Main site or cell type	Ferroptosis-related molecular mechanisms	Reported effect	n/group	Sex	Dose	Duration	Behavioral	Rescue	Cell-Specific	Evidence	Ref
Quercetin	Breast cancer-related depression; perimenopausal depression; OVX-CUMS model	Neurons, PFC, hippocampus, hypothalamus	Regulated PTGS2/COX-2, lipid metabolism, acetyl-H3K9-related ferroptosis, ER stress markers, SLC7A11, and GPX4	Alleviated depressive-like behavior and ferroptosis-related metabolic injury	n = 5/group [4]; n = 12/group [5]; n = 12/group [6]	Female BALB/c; Female Wistar; Female Wistar	4, 8 mg/kg [4]; 50 mg/kg·bw [5]; 50 mg/kg·bw [6]	25 days; 4 weeks; 4 weeks	FST, TST, SPT, OFT, NOR, NSF; FST, TST, SPT, OFT, EPM, NOR, NSF; FST, SPT, OFT, EPM, NOR, NSF	PTGS2 overexpression; siRNA; none	Neuron; Astrocyte; Whole-tissue	I	[[4], [5], [6]]
Cynaroside	CUMS model	Microglia/hippocampus	Inhibited IRF1/SLC7A11/GPX4-mediated microglial ferroptosis and inflammation	Improved depressive-like behavior and reduced microglial inflammatory activation	n = 6/group	Male	10, 20, 30, 40 mg/kg CNS	7 weeks CUMS + 2 weeks drug	FST, TST, SPT, OFT, EPM, NSF	none	Microglia	I	[7]
Sinensetin	Post-stroke depression	Brain tissue/inflammatory and ferroptotic pathways	Dual regulation of TLR4/NF-κB and Nrf2/GPX4 pathways	Attenuated PSD-related depressive-like behavior	n = 10/group	Male	25 and 50 mg/kg, oral, daily for 14 days	14 days	SPT, TST, FST	none	Whole-tissue	I	[8]
Baicalin	Atherosclerosis-associated depression	Neurons; gut microbiota–lipid metabolism axis	Modulated gut microbiota and lipid metabolism; inhibited neuronal ferroptosis	Improved depression-like behavior in AS comorbidity model	n = 16/group (behavioral), n = 6/group (molecular)	Male C57 (C57BL/6J + ApoE−/−)	Baicalin 50, 100 mg/kg	16 weeks	TST, SPT, OFT, NOR, NSF	none	Neuron	I	[9]
Resveratrol	Ferroptosis-related depression model; erastin-treated PC12 cells	Hippocampus/neuronal cells	Activated AKT/Nrf2 signaling; restored GPX4-related antioxidant defense; reduced ferroptosis markers	Alleviated depression-like behaviors and neuronal ferroptotic injury	n = 9–10/group	Male	80 mg/kg i.g. daily	4 weeks	FST, SPT, OFT, NSF	ML385, erastin	Whole-tissue	I	[10]
Gallic acid	Chronic pain and depression comorbidity	Spinal cord	Inhibited P2X7 receptor-mediated ferroptosis	Improved comorbid chronic pain and depression-like behaviors	n = 10/group	Male	100 mg/kg for 2 weeks from the 4th week	2 weeks	FST, SPT, OFT, NSF	P2X7 shRNA	Microglia	III	[11]
Pellitorine	Chronic restraint stress model	Brain tissue/neuroinflammatory context	Reduced neuroinflammation and ferroptosis-related injury	Protected against CRS-induced cognitive and affective impairment	n = 9/group	Male C57BL/6J	0.1, 0.6 mg/kg i.p.	35 days (5 weeks)	TST, SPT, OFT, NOR, MWM	none	Microglia	I	[12]
Saikosaponin B2	Depression-induced microglial activation	Microglia	Suppressed GPX4-dependent ferroptosis, Fe²⁺ accumulation, lipid peroxidation, ER stress, and TLR4/NF-κB signaling	Reduced microglial activation and depressive-like pathology	n = 10/group	Male ICR	10 mg/kg	not reported	SPT, OFT, TST, FST	GPX4-KD	Microglia	III	[13]
Asiaticoside	Chronic restraint stress model	Hippocampal CA1 neurons	Activated BDNF/Nrf2/GPX4 signaling; increased SLC7A11 and GPX4; reduced TFR1, lipid ROS, and mitochondrial injury	Attenuated hippocampal neuronal ferroptosis and depressive-like behavior	n = 11/group	Male ICR	20 mg/kg in 10 mL/kg once daily	28 days	OFT, SPT, FST, NOR, NSF	GPX4-KD	Neuron	III	[14]
Gypenosides	CORT-induced PC12 cell injury	PC12 neuronal cells	Inhibited TNF-α/NF-κB signaling and CORT-induced ferroptosis	Reduced neuronal ferroptotic injury under glucocorticoid stress	n = 6 (in vitro)	N/A (in vitro)	150 μg/mL	N/A	N/A (in vitro)	DFO, Ferrostatin-1	PC12 cells	II	[15]
Atractylodin	CUMS model	Hippocampus	Increased GPX4, SLC7A11, BDNF, and Nrf2; reduced ROS, MDA, IL-1β, and TNF-α	Alleviated depressive-like behavior and hippocampal neuronal injury	n = 10/group	Male	10, 20, 40 mg/kg	4 weeks	FST, OFT, NOR	none	Whole-tissue	I	[16]
HSYA	CUMS model	Microglia/hippocampus	Activated SIRT1 and modulated SIRT1/Nrf2/NF-κB signaling; reduced microglial activation and ferroptosis	Reduced depressive-like behaviors and neuroinflammation	n = 6/group	Male SD rats	15, 30, 60 mg/kg	4 weeks	TST, OFT, EPM, NSF	none	Microglia	I	[17]
Bufotenidine	CORT-induced depressive-like model	Astrocytes and glutamatergic neurons	Targeted GluA1; reduced neuronal lipid synthesis and astrocytic ferroptosis	Alleviated depressive-like behavior through astrocyte–neuron metabolic regulation	n = 8/group	Male	Bufotenidine 5, 15 mg/kg; CORT 40 mg/kg	CORT 4 weeks + drug 1 week	FST, TST, SPT, OFT, NSF	Fer-1, DFO	Astrocyte	II	[18]
Spinosin	Depression-related model involving synaptic plasticity	Synaptic and ferroptosis-related pathways	Regulated PTP1B-associated coordination of synaptic plasticity and ferroptosis	Produced antidepressant-like effects	n = 15/group	Male ICR	5, 10 mg/kg	35 days	FST, TST, SPT, OFT, NSF	Erastin, K252a, PTP1B overexpression	Whole-tissue	III	[19]
LBGP	Stress-induced anxiety/depression-related model	Medial prefrontal cortex	Regulated oxidative stress and ferroptosis-related markers	Prevented stress-induced anxiety-like and affective abnormalities	n = 5/group	Male C57BL/6J	10 mg/kg/day	14 days	OFT, FST, TST, SPT	GPX4-KD	Whole-tissue	III	[20]
AP (Atractylodes polysaccharide)	Chemotherapy-induced depression-like behavior	Gut–brain axis; intestinal barrier	Reduced intestinal ferroptosis, improved gut barrier injury, and regulated gut microbiota/metabolites	Alleviated chemotherapy-induced depressive-like behavior	n = 10/group	Female C57BL/6	AP 0.1, 0.3 g/kg/day orally; Pirarubicin 5 mg/kg/wk i.p.	AP daily + pirarubicin weekly (duration NR)	OFT, EPM, FST, TST, SPT, NOR	Antibiotic gut depletion	Multi-tissue (gut + brain)	II	[21]
Seahorse extract	DSS-induced depression-like model	Hippocampus	Increased pNrf2, HO-1, GPX4, and SLC7A11; reduced neuroinflammation and ferroptosis	Attenuated DSS-induced depressive-like behavior	n = 10/group	Male C57BL/6	Seahorse 0.65 g/kg; Fluoxetine 20 mg/kg (positive control)	DSS + treatment period (NR)	FST, SPT, OFT, NOR	none	Microglia	I	[22]
Xiaoyaosan	CUMS model	Hippocampus	Regulated PEBP1/GPX4-mediated ferroptosis; reduced iron accumulation and lipid peroxidation	Improved CUMS-induced depressive-like behavior	12 (48 mice/4 groups)	Male	0.254 g/kg/d (intragastric)	6 weeks (CUMS), medication from 4th to 6th week	FST, SPT, OFT, NSF	none	Whole-tissue	I	[23]
Di-Huang-Yin-Zi	Post-stroke depression	Hippocampus/neuronal ferroptosis	Regulated p53/SLC7A11 signaling	Ameliorated PSD-related depressive-like behavior	n = 12/group	Male SD	0.2, 0.4, 0.8 g/kg	21 days	SPT, FST, OFT, NOR	P53 overexpression	Whole-tissue	II	[24]
YNJY	Post-stroke depression	Hippocampal neurons	Activated Nrf2/GPX4/SLC7A11 pathway; anti-ferroptotic effect weakened by Nrf2 inhibition	Reduced hippocampal neuronal ferroptosis and PSD symptoms	n = 10/group (behavioral), n = 3–6/group (molecular)	NR	YNJY 4.19, 8.38 g/kg/day; ML385 30 mg/kg/day i.p.	CUMS + treatment period (NR)	FST, TST, SPT, OFT, NOR, NSF	Nrf2 siRNA	Neuron	III	[25]
KXS (Kaixinsan)	Adriamycin-induced depression-like behavior	Prefrontal cortex	Reduced prefrontal cortical ferroptosis	Alleviated chemotherapy-associated depressive-like behavior	n = 10/group	Female BALB/c	Kaixinsan low/high dose + Adriamycin 5 mg/kg (day 1,7,14,21)	Adriamycin + Kaixinsan treatment period	OFT, EPM	Ferrostatin-1 (Fer-1)	NR	II	[26]
Bushen Shugan Huayu formula	Perimenopausal depression	Neurons	Regulated neuronal ferroptosis through GPER1/Nrf2 pathway	Improved depressive-like behavior in perimenopausal mice	n = 10/group	Female C57BL/6J (OVX)	6.5, 13, 26 g/kg BW	28 days	FST, SPT, OFT, NSF	ER-KO, siRNA	Neuron	III	[27]
BDDSD	Depression with myocardial ischemia–reperfusion injury	Peripheral heart tissue in depression context	Inhibited ferroptosis-related myocardial injury	Alleviated depression-aggravated myocardial ischemia–reperfusion injury	n = 12/group	Male SD	10.1 g/kg/day	6 weeks CUMS, BDDSD during final 2 weeks	OFT, EPM, SPT, FST	none	Whole-tissue	I	[28]
Acupuncture	CUMS model	Hippocampus; microglia and astrocytes	Restored SIRT1/Nrf2/HO-1/GPX4 signaling; reduced MDA, IL-1β, IL-6, TNF-α; improved SOD, GSH, GSH-Px, and T-AOC	Reduced oxidative stress, neuroinflammation, ferroptosis, and depressive-like behavior	n = 9/group	Male	Acupuncture (no drug); Fluoxetine 2.1 mg/kg (comparator)	4 weeks CUMS + 28 days acupuncture	SPT, OFT, EPM, NOR, NSF	none	Whole-tissue	I	[29]
EA (electroacupuncture)	PSD; chronic inflammatory pain with depression; SCI-associated depression; early-life CSD-induced adult depression-like behavior	PFC neurons, hippocampal neurons, SCI-related brain alterations	Inhibited ferroptosis through Nrf2, SIRT1/HMGB1, and circadian autophagy-related pathways; reduced iron deposition and lipid peroxidation	Improved depressive-like behaviors across multiple models	n = 12/group; n = 10/group	Male SD; Male SD	N/A (electroacupuncture); ML385/Fer-1 10 mg/kg	not reported; 3 days	SPT, OFT, FST; SPT, FST, social interaction	Fer-1; GA (HMGB1 inhibitor)	Neuron; Whole-tissue	II; II	[30,31]
“Shugan Tiaoshen” acupuncture	Chronic inflammatory pain and depression comorbidity	Hippocampal neurons	Regulated hippocampal iron metabolism, antioxidant system, and lipid peroxidation-related factors	Improved pain–depression comorbidity and protected hippocampal neurons	12/group	Male	Paroxetine 10 mg/kg (positive control)	14 days	SPT, OFT, FST	none	Neuron	I	[32]
TPM (pediatric massage)	CUMS-exposed adolescent rats	Hippocampus/microglia-related inflammatory environment	Activated IGF-1/Nrf2 pathway; regulated neuroinflammation and antioxidant defense	Produced antidepressant-like effects and enhanced stress resilience	n = 8/group (5 groups)	Male	N/A (massage); PPP 10 mg/kg i.p. (IGF-1R inhibitor)	3 weeks CUMS + 28 days TPM	SPT, OFT, EPM, MWM, NOR, NSF	Picropodophyllin (IGF-1R inhibitor)	Microglia	II	[33]

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Note. Evidence level: I = biochemical marker association only (changes in ferroptosis markers such as GPX4, MDA, or GSH without causal validation); II = pharmacological rescue validation (ferroptosis inhibitors such as Ferrostatin-1 or deferoxamine, or activators such as erastin, used to confirm reversibility of the observed effect); III = genetic validation (knockout, knockdown, siRNA/shRNA silencing, or overexpression confirming a causal role). Multiple evidence levels separated by semicolons indicate that different experiments within the same study achieved different levels of validation.

Abbreviations: AP, Atractylodes macrocephala polysaccharide; BDDSD, Baihe Dihuang Danshen decoction; CID, chemotherapy-induced depression; CORT, corticosterone; CSD, chronic social defeat; CUMS, chronic unpredictable mild stress; DFO, deferoxamine; DSS, dextran sulfate sodium; EA, electroacupuncture; EPM, elevated plus maze; Fer-1, Ferrostatin-1; FST, forced swim test; GF, germ-free (antibiotic-depleted); GPX4-KD, GPX4 knockdown; HSYA, hydroxysafflor yellow A; KXS, Kaixinsan; LBGP, Lycium barbarum glycopeptide; MWM, Morris water maze; NOR, novel object recognition; NR, not reported; NSF, novelty suppressed feeding; OFT, open field test; OVX, ovariectomized; PSD, post-stroke depression; SCI, spinal cord injury; SPT, sucrose preference test; TPM, traditional pediatric massage; TST, tail suspension test; YNJY, Yi-Nao-Jie-Yu prescription.

Table 2.

Pharmacological agents and biomedical interventions targeting ferroptosis in depression-related models.

Intervention (category)	Model/context	Main site or cell type	Ferroptosis-related molecular mechanisms	Reported effect	Ref
Edaravone (free-radical scavenger, repurposed)	Chronic social defeat stress model	Brain tissue	Activated SIRT1/Nrf2/HO-1/GPX4 pathway; effects weakened by Nrf2 inhibition	Alleviated CSDS-induced depressive- and anxiety-like behaviors	[34]
Melatonin (hormone-like agent)	LPS-induced depressive-like model	Brain tissue	Regulated RNA methylation-mediated SIRT6/Nrf2/HO-1 pathway; increased GPX4 and FTH1	Alleviated LPS-induced depressive-like behavior	[35]
Nicorandil (repurposed cardiovascular drug)	Traumatic brain injury-associated depressive-like behavior	Hippocampus	Suppressed ferroptosis through SLC7A11/GPX4 axis	Ameliorated TBI-induced depression-like behaviors	[36]
Rebamipide (repurposed gastroprotective drug)	Letrozole (PCOS)-induced depressive-like behavior	Brain tissue	Targeted SIRT1/FoxO1/Wnt/β-catenin signaling and ferroptosis-related pathways	Alleviated letrozole-induced depressive-like behavior in female rats	[37]
Ketamine (rapid-acting antidepressant)	Chronic restraint stress model	Habenular nucleus	Regulated neuroplasticity, autophagy, and ferroptosis-related pathways	Exerted rapid antidepressant effects	[38]
Etomidate (i.v. anesthetic, ECT adjunct)	CUMS model combined with electroconvulsive therapy	Hippocampal neurons	Upregulated BDNF/Nrf2 signaling and inhibited neuronal ferroptosis	Improved the antidepressant effect of ECT	[39]
Ferrostatin-1 (rescue in tsRNA-3029b study)	CUMS model (tsRNA-3029b study)	Neurons	Inhibited ferroptosis; restored SLC7A11 and GPX4	Alleviated CUMS-induced depression	[40]
Deferoxamine (rescue in nanoplastics model)	Realistic nanoplastic-induced depressive-like behavior	Mitochondrial iron overload context	Chelated iron; reduced mitochondrial iron overload, ferritinophagy, lipid peroxidation	Reversed nanoplastic-induced depression (as ferroptosis rescue)	[41]
GLX351322-loaded nanoparticles (NOX4-targeting)	Chronic stress-induced depressive-like behavior	Neurons	Inhibited NOX4/Nrf2/HO-1/GPX4-related oxidative stress and ferroptosis	Alleviated chronic stress-induced depressive behaviors	[42]
H₂S/NaHS (gasotransmitter donor)	Type 1 diabetes-associated anxiety/depression-like behaviors	Systemic metabolic and inflammatory context	Inhibited inflammation and ferroptosis-related injury	Alleviated type 1 diabetes-associated anxiety/depression-like behaviors	[43]
l-Se-methylselenocysteine (selenium compound)	Chronic renal failure rats receiving iron therapy	Brain iron deposition context	Activated Nrf2/GPX4 pathway; reduced iron deposition-induced ferroptosis	Alleviated iron deposit-induced anxiety/depression-like behaviors	[44]
Hyperbaric oxygen (biomedical intervention)	Spinal cord injury-associated depression and cognitive impairment	Brain tissue after SCI	Regulated Nrf2/GPX4 signaling; reduced neuroinflammation, oxidative stress, ferroptosis	Protected against SCI-associated depression and cognitive impairment	[45]

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Table 3.

Gut microbiota-derived metabolites and dietary lipids targeting ferroptosis in MDD.

Intervention	Model/context	Main site or cell type	Ferroptosis-related molecular mechanisms	Reported effect	n/group	Sex	Dose & Route	Duration	Behavioral	Rescue	Evidence	Ref
Butyric acid/butyrate	Stress-induced depression-like models; acute stress model	Hippocampus, PFC, gut–brain axis	Restored SLC7A11/GPX4 axis; reduced iron accumulation, lipid peroxidation, neuroinflammation, intestinal and BBB injury	Attenuated stress-induced depressive-like behavior	n = 6/group	Male C57BL/6J	Butyrate 1200 mg/kg/day oral gavage; Valerate 15 mg/kg/day oral gavage; 30 min prior to restraint	3 days (acute)	TST, OFT, NOR, NSF	Fer-1 (10 mg/kg), DFO (100 mg/kg)	II	[46]
Valeric acid	Stress-induced depression-like model	Hippocampus	Suppressed hippocampal neuroinflammation and ferroptosis-related abnormalities	Reduced stress-induced depressive-like behavior	n = 6/group	Male C57BL/6J	Valerate 15 mg/kg/day oral gavage; 30 min prior to restraint	7 days (chronic)	TST, OFT, NOR, NSF	Fer-1, DFO	II	[46]
IPA	Depression-aggravated myocardial ischemia–reperfusion injury	Brain–gut–heart axis; peripheral myocardial tissue	Activated Nrf2/System Xc⁻/GPX4 axis; reduced oxidative stress and ferroptosis	Reduced depression-associated aggravation of myocardial injury	n = 3-8/group	Male C57BL/6	IPA 20 mg/kg BW daily oral gavage; Tryptophan 2 g/kg BW daily oral gavage	10 days (IPA gavage); 10 days CSDS; MI/R after	FST, TST, SPT, SIT (social interaction)	Nrf2 siRNA, NAC	III	[47]
DHA	Chronic sleep deprivation-induced depressive-like behavior; PTZ-kindling with depressive-like behavior	Oligodendrocytes, neuroimmune environment	Regulated iron metabolism, oligodendrocyte lipid peroxidation, and LCN2/NLRP3 signaling	Alleviated depressive-like behavior and neuroinflammation	n = 8/group (behavioral), n = 3/group (molecular)	Female C57BL/6	1% DHA in diet (w/w)	21 days SD + DHA supplementation	FST, OFT, MWM, NOR, NSF	Fer-1, DFO	II	[48,49]
EPA	Chronic sleep deprivation-induced depressive-like behavior; PTZ-kindling with depressive-like behavior	Oligodendrocytes, microglia/neuroimmune environment	Regulated iron metabolism, oligodendrocyte lipid peroxidation, M2 microglial polarization, and LCN2/NLRP3 axis	Improved depressive-like behavior, with stronger effect than DHA in CSD model	n = 8/group (behavioral), n = 3/group (molecular)	Female C57BL/6 (SD); Male ICR (PTZ)	1% EPA in diet (w/w)	21 days SD + EPA supplementation; PTZ kindling period	FST, OFT, MWM, NOR, NSF	Fer-1, DFO	II	[48,49]

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Note. Evidence level: I = biochemical marker association only; II = pharmacological rescue validation (ferroptosis inhibitors such as Ferrostatin-1 or deferoxamine used to confirm reversibility); III = genetic validation (knockout, knockdown, siRNA silencing, or overexpression confirming a causal role). NR = not reported.

Abbreviations: CSD, chronic sleep deprivation; CSDS, chronic social defeat stress; DFO, deferoxamine; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; Fer-1, Ferrostatin-1; IPA, indole-3-propionic acid; MI/R, myocardial ischemia-reperfusion; MWM, Morris water maze; NAC, N-acetylcysteine; NOR, novel object recognition; NSF, novelty suppressed feeding; OFT, open field test; PTZ, pentylenetetrazol; SD, sleep deprivation; SPT, sucrose preference test; TST, tail suspension test.

The pathogenesis of depression remains incompletely understood. Over the past decades, multiple processes have been implicated, including monoaminergic dysregulation, hypothalamic–pituitary–adrenal axis disturbance, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired neuroplasticity [50]. Rather than acting in isolation, these abnormalities appear to interact within a complex pathological network [51]. In recent years, increasing attention has been directed toward forms of regulated cell death that may participate in this network and contribute to cellular dysfunction in the depressive brain [52].

Ferroptosis, first described in 2012, is an iron-dependent form of regulated cell death driven by excessive lipid peroxidation and failure of intracellular antioxidant defense systems [53]. Unlike apoptosis, necrosis, or autophagy, ferroptosis is characterized by distinct metabolic and biochemical features, particularly abnormal iron handling, phospholipid peroxide accumulation, and dysfunction of pathways such as System Xc⁻/glutathione (GSH)/glutathione peroxidase 4 (GPX4) [54]. Because the brain is highly enriched in polyunsaturated lipids, consumes large amounts of oxygen, and depends on finely regulated redox balance, it may be especially vulnerable to ferroptosis-related injury under pathological conditions [55]. Furthermore, growing evidence has linked. Studies in stress-related animal models have reported iron accumulation, increased lipid peroxidation, glutathione depletion, reduced GPX4 or Solute Carrier Family 7 Member 11 (SLC7A11) expression, and behavioral abnormalities resembling depressive phenotypes [56]. In parallel, clinical and bioinformatic studies have identified depression-associated changes in oxidative status, iron metabolism, and ferroptosis-related molecular signatures. These observations have brought ferroptosis into the discussion of depression pathophysiology, not only at the level of neuronal injury, but also in relation to microglial activation, astrocytic dysfunction, and disturbances in the brain microenvironment [57].

This emerging understanding has also expanded interest in the therapeutic implications of ferroptosis in depression. In recent years, diverse strategies have been explored to modulate ferroptosis-related pathways, including chemical agents, specific ferroptosis inhibitors, and naturally derived compounds, all of which have shown potential in experimental studies of depression. Among them, natural products have received increasing attention because of their multi-component and multi-target characteristics. In this review, we summarize the molecular basis of ferroptosis in the context of depression, discuss its potential involvement across different brain cell populations and pathological networks, and further examine current progress in ferroptosis-targeted therapeutic strategies, with particular attention to natural products.

2. Molecular basis of ferroptosis relevant to depression

2.1. Iron dyshomeostasis and expansion of the labile iron pool

Iron dyshomeostasis is a central upstream event in ferroptosis. The core metabolic pathways reviewed in this section are summarized in Fig. 1. Under physiological conditions, cellular iron homeostasis is maintained by a coordinated network controlling iron uptake, intracellular trafficking, storage, and export [58]. In the canonical transferrin-bound iron pathway, transferrin (TF) carries ferric iron (Fe³⁺) in the circulation and binds to transferrin receptor 1 (TFR1) on the plasma membrane [59]. The TF–TFR1 complex is then internalized through endocytosis, and acidification of the endosome promotes Fe³⁺ release. Within the endosomal lumen, six-transmembrane epithelial antigen of prostate 3 (STEAP3) reduces Fe³⁺ to ferrous iron (Fe²⁺), which is subsequently transported into the cytosol by divalent metal transporter 1 (DMT1) [60]. In addition to this tightly regulated route, excess iron may also enter cells as non-transferrin-bound iron (NTBI) through alternative transporters such as solute carrier family 39 member 8 (SLC39A8; also known as ZIP8) and solute carrier family 39 member 14 (SLC39A14; also known as ZIP14), thereby bypassing part of the canonical transferrin-dependent checkpoint system [61,62]. Once released into the cytoplasm, Fe²⁺ enters the labile iron pool (LIP), a redox-active iron compartment that is metabolically useful but potentially toxic when expanded excessively [63].

To prevent iron-mediated toxicity, excess intracellular iron is normally sequestered within ferritin, a heteropolymer mainly composed of ferritin heavy chain 1 (FTH1) and ferritin light chain (FTL) [64]. Ferritin stores iron in a relatively inert form and thus limits the size of the redox-active LIP. However, this buffer can be dismantled by ferritinophagy, a selective autophagic process mediated by nuclear receptor coactivator 4 (NCOA4), which delivers ferritin to lysosomes for degradation and releases stored iron back into the cytosol [65]. Iron export is mediated by ferroportin 1 (FPN), currently the only established cellular iron exporter, and its abundance is negatively regulated by hepcidin antimicrobial peptide (HAMP), which induces FPN internalization and degradation [66]. Ferroptosis is favored when this network shifts toward iron retention—that is, when iron uptake increases, ferritin buffering is weakened, ferritinophagy is enhanced, or ferroportin-dependent efflux is suppressed [67]. Excess Fe²⁺ can promote Fenton chemistry and increase the generation of reactive oxygen species (ROS), thereby creating a redox environment that favors lipid peroxidation and ferroptotic cell damage [68].

In the setting of MDD, increasing evidence suggests that this iron-regulatory network may become destabilized rather than simply shifted toward uniform iron overload. Neuroimaging studies using quantitative susceptibility mapping have reported higher magnetic susceptibility values in the putamen and thalamus of patients with major depressive disorder, consistent with altered regional brain iron deposition, while longitudinal work in late-life depression has linked progressive changes in iron deposition to disease course [69,70]. In parallel, experimental depression models have associated depressive-like behavior with hippocampal iron accumulation, Fe²⁺ elevation, impaired antioxidant defense, and disruption of ferroptosis-related signaling [71]. These findings suggest that, in depression, chronic stress and related metabolic disturbances may reshape iron trafficking at multiple levels—including uptake, storage, ferritin turnover, and efflux—thereby expanding the redox-active iron pool and sensitizing stress-vulnerable brain regions to ferroptotic injury. For this reason, the term iron dyshomeostasis is more appropriate than simple iron overload when discussing ferroptosis in depression.

2.2. Lipid peroxidation and phospholipid remodeling

Lipid peroxidation is the core execution event of ferroptosis. In contrast to generalized oxidative injury, ferroptotic lipid damage is centered on polyunsaturated fatty acid (PUFA)-containing phospholipids, especially arachidonic acid (AA)- and adrenic acid (AdA)-containing membrane species [72]. Free AA or AdA must first be activated to acyl-CoA derivatives by acyl-CoA synthetase long-chain family member 4 (ACSL4), generating AA-CoA and AdA-CoA [73]. These activated PUFAs are then esterified into membrane phosphatidylethanolamine (PE) by lysophosphatidylcholine acyltransferase 3 (LPCAT3), thereby enriching cellular membranes with oxidizable PUFA-PE substrates [74]. This lipid-remodeling step is crucial, because ferroptosis sensitivity depends not simply on total lipid abundance, but on the presence of specific PUFA-phospholipid species that can undergo peroxidation. Consistent with this, ACSL4 has been shown to dictate ferroptosis sensitivity by shaping cellular lipid composition, and oxidized AA/AdA-containing PE species have been identified as proximate execution signals of ferroptotic death [75].

It is important to distinguish nonspecific oxidative markers from ferroptosis-specific evidence. Malondialdehyde (MDA), bulk reactive oxygen species (ROS), 4-HNE protein adducts, and C11-BODIPY 581/591 fluorescence signals are readouts of lipid peroxidation rather than ferroptosis-specific markers: they can arise from multiple oxidative and non-ferroptotic pathways and therefore do not unambiguously indicate ferroptosis. Stronger ferroptosis attribution requires convergent evidence combining iron dependence, dysfunction of the System Xc⁻/GSH/GPX4 axis, and confirmation by pharmacological rescue (e.g., Ferrostatin-1 or deferoxamine) or genetic validation. The most ferroptosis-selective readouts are oxidized arachidonic acid- and adrenic acid-containing phosphatidylethanolamines (AA-PE and AdA-PE) detected by untargeted lipidomic profiling. Throughout this review, we note where specific versus nonspecific markers are used and whether the cited evidence meets these convergent criteria.

Once PUFA-PE species are formed, they can be oxidized through both non-enzymatic and enzymatic routes [76]. In the non-enzymatic route, redox-active Fe²⁺ promotes radical chain reactions that convert phospholipids into phospholipid hydroperoxides (PLOOHs) [77]. In the enzymatic route, arachidonate 15-lipoxygenase (ALOX15) plays a major role, particularly when associated with phosphatidylethanolamine-binding protein 1 (PEBP1; also known as Raf kinase inhibitory protein, RKIP), which helps redirect ALOX15 activity toward PE oxidation [78]. This process generates pro-ferroptotic oxidized phospholipids such as PE-AA-OOH and PE-AdA-OOH, which destabilize membrane structure and function. In many ferroptosis settings, increased prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase-2 (COX-2) is also observed as a downstream oxidative stress marker, although it is generally regarded as an associated indicator rather than the direct executor of lipid peroxidation [79].

In MDD, this mechanism is especially relevant because the brain is highly enriched in oxidizable membrane lipids and is exposed to sustained oxidative and inflammatory stress under chronic stress conditions [80]. Clinical studies have linked major depression, including treatment-resistant phenotypes, with increased lipid peroxidation, while experimental depression models provide more direct ferroptosis-related evidence. In chronic unpredictable mild stress (CUMS) mice, ferroptosis-related alterations in ACSL4, GPX4, FTH1, and COX-2/PTGS2 expression have been documented alongside depressive-like behavior [23]. More specifically, a recent corticosterone-related study showed that chronic stress promotes ALOX15–PEBP1-dependent phospholipid peroxidation, leading to loss of hippocampal neural stem cells and depressive-like phenotypes [81,82]. These findings suggest that, in the depressive brain, lipid peroxidation is not merely a nonspecific oxidative byproduct, but a mechanistically organized process that can connect chronic stress to ferroptotic injury.

2.3. Failure of the System Xc⁻/GSH/GPX4 antioxidant axis

Among the metabolic checkpoints that restrain ferroptosis, the System Xc⁻/GSH/GPX4 axis is the most direct phospholipid peroxide–detoxifying pathway [83]. System Xc⁻ is a sodium-independent cystine/glutamate antiporter composed of the light-chain SLC7A11 and the heavy-chain subunit solute carrier family 3 member 2 (SLC3A2) [84]. This transporter imports extracellular cystine (Cys2) in exchange for intracellular glutamate (Glu) [85] After entering the cell, cystine is rapidly reduced to cysteine (Cys), which serves as the rate-limiting substrate for GSH biosynthesis [86]. GSH synthesis proceeds through two ATP-dependent enzymatic steps: first, glutamate-cysteine ligase (GCL)—consisting of a catalytic subunit GCLC and a modifier subunit GCLM—generates γ-glutamylcysteine; second, glutathione synthetase (GSS) converts this intermediate into GSH [87]. GPX4, a selenium-dependent phospholipid hydroperoxidase, then uses GSH as a reducing cofactor to convert toxic PLOOHs into non-toxic phospholipid alcohols (PLOHs), thereby preventing the propagation of membrane lipid peroxidation [88]. During this reaction, GSH is oxidized to glutathione disulfide (GSSG), which can be recycled back to GSH by glutathione reductase (GSR) using nicotinamide adenine dinucleotide phosphate (NADPH) as an electron donor [89].

This axis is also shaped by multiple upstream regulators that determine ferroptosis sensitivity. Under oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) and activating transcription factor 4 (ATF4) can transcriptionally upregulate SLC7A11 and other antioxidant genes, thereby enhancing cystine utilization and GSH synthesis [90]. By contrast, tumor protein p53 (TP53) can repress SLC7A11 transcription under certain conditions, sensitizing cells to ferroptosis. In parallel, NADPH availability is critical because it supports GSH regeneration through GSR, linking the anti-ferroptotic system to broader cellular redox metabolism [91]. Cells may partially compensate for cystine limitation through the transsulfuration pathway, in which methionine-derived sulfur is converted to cysteine via enzymes such as cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH/CSE); however, this backup route is often insufficient when oxidative demand is high [92]. Accordingly, ferroptosis is promoted when cystine import is impaired, cysteine becomes limiting, GSH is depleted, GPX4 is inactivated, or NADPH-dependent recycling fails. Under these conditions, phospholipid hydroperoxides accumulate beyond the detoxification threshold and ferroptotic membrane damage ensues [93].

In MDD, disruption of this antioxidant axis is one of the most consistently reported ferroptosis-related abnormalities. Experimental studies in CUMS models have repeatedly shown reduced hippocampal SLC7A11 and GPX4 expression together with increased iron or lipid peroxidation and depressive-like behaviors; interventions such as cynaroside, hydroxysafflor yellow A, and acupuncture restore SLC7A11/GPX4 signaling while improving behavioral phenotypes [7,17,29]. More broadly, depression has long been linked to oxidative stress and glutamatergic dysregulation, both of which are directly relevant to System Xc⁻ function: limited cystine uptake constrains GSH synthesis, whereas disturbed glutamate homeostasis may further compromise antiporter activity and redox balance [94]. Human studies also suggest that glutathione abnormalities are present in depressive disorders, although the direction and magnitude of change may vary across cohorts and brain regions [95]. Taken together, these findings support the view that, in depression, failure of the System Xc⁻/GSH/GPX4 defense line is not merely a downstream consequence of stress, but a plausible molecular route through which chronic stress is translated into persistent phospholipid peroxidation and ferroptotic vulnerability in mood-related brain regions. The net effect of System Xc⁻/SLC7A11 activity depends on the balance between cystine uptake (supporting GPX4-dependent detoxification) and glutamate efflux (potentially exacerbating excitotoxicity), and this balance is cell-type-dependent. In astrocytes, SLC7A11 contributes to extracellular cysteine supply for neighboring neurons, and astrocytic EAAT1 (GLAST) and EAAT2 (GLT-1) buffer the exported glutamate. In neurons and microglia, the protective-versus-toxic balance may differ. Accordingly, “restoring SLC7A11/GPX4 signaling” should be understood as context-dependent and cell-type-specific rather than as a universally protective intervention. The observed iron-related alterations in MDD are best characterized as iron dyshomeostasis rather than uniform iron overload and should not be taken as evidence of a simple ‘depression-equals-iron-accumulation’ model.

2.4. Human evidence: peripheral and central biomarkers in patients with MDD

Although most mechanistic evidence for ferroptosis in depression comes from animal models, a growing body of clinical research has examined ferroptosis-related biomarkers in patients with MDD. These human studies provide a crucial translational bridge between preclinical observations and clinical relevance, but should be interpreted with the understanding that available human data are largely observational, correlational, and derived from peripheral compartments or indirect neuroimaging measures that cannot directly confirm ferroptotic cell death in the living human brain.

Iron status and peripheral markers. Early clinical work reported disturbances of iron metabolism in MDD, including reduced serum iron and transferrin alongside elevated serum ferritin, findings interpreted as reflecting chronic inflammatory iron sequestration rather than systemic iron deficiency [96]. Several meta-analyses confirmed elevated malondialdehyde (MDA) in depression [97], and a meta-analysis reported reduced total glutathione (GSH) levels in MDD patients, consistent with impaired antioxidant capacity [95]. These peripheral findings align with the iron dyshomeostasis and lipid peroxidation themes outlined in Sections 2.1-2.2, although they reflect systemic rather than brain-specific processes.

Brain iron imaging. Quantitative susceptibility mapping (QSM) and related MRI techniques permit non-invasive estimation of regional brain iron deposition in vivo. In recurrent depression, multiple regions including the putamen, thalamus, caudate, and amygdala showed increased QSM values, indicating elevated brain iron content [98,99]. Additional studies extended these findings to late-life depression and to the habenula, brainstem, and cerebellum [100,101]. These imaging data provide some of the most direct human evidence for altered brain iron handling in MDD, although QSM-measured iron reflects total iron content and cannot distinguish between functional (labile) and stored (ferritin-bound) iron pools.

Transcriptomic and multi-omics evidence. Human peripheral blood omics studies have begun to nominate ferroptosis-associated pathways in MDD. A recent multi-omics analysis integrating blood expression quantitative trait loci (eQTLs), depression genome-wide association data, and single-cell eQTL mapping in peripheral immune cells identified 42 ferroptosis-related genes associated with depression and pinpointed ribosomal protein RPL8 as a protective factor [102]. Although such omics-level findings are hypothesis-generating rather than confirmatory, and their associations with ferroptosis remain correlational rather than causal, they add molecular-level human support to the preclinical ferroptosis framework.

In summary, human studies in MDD converge on increased lipid peroxidation (MDA), altered iron handling (ferritin, brain iron on QSM), and reductions in antioxidant defences (GSH), consistent with a state of heightened oxidative stress and iron dyshomeostasis that overlaps substantially with the ferroptosis phenotype described in preclinical models. However, these clinical findings remain correlational and should not be equated with confirmed ferroptotic cell death. Future work should incorporate ferroptosis-specific circulating markers (e.g., ACSL4, GPX4 activity), longitudinal designs, and integration with multimodal neuroimaging to strengthen the human evidence base for ferroptosis in MDD.

3. Evidence linking ferroptosis to MDD: vulnerable brain regions, cellular involvement, and pathological networks

The evidence reviewed in this section is heterogeneous in origin and should not be treated as a single, interchangeable body of proof. For clarity, we organize it into three tiers. Tier I comprises MDD patient studies, including brain iron imaging (quantitative susceptibility mapping), peripheral biomarker analyses, and transcriptomic investigations. Tier II consists of classical depression-like models such as chronic unpredictable mild stress (CUMS), corticosterone (CORT) exposure, and lipopolysaccharide (LPS) challenge. Tier III includes comorbidity-associated models such as post-stroke depression (PSD), traumatic brain injury (TBI)-associated depression, diabetes-associated depression, pain-associated depression, sleep deprivation, and chemotherapy-associated depression. Throughout this section, we flag the evidence tier where relevant to facilitate source-aware interpretation.

Before reviewing the MDD evidence, we note that reduced GPX4 or SLC7A11, elevated malondialdehyde (MDA), and regional iron deposition are best interpreted as ferroptosis-related or ferroptosis-compatible alterations rather than as definitive proof of ferroptotic cell death. These markers, while informative, overlap substantially with classical oxidative stress and non-ferroptotic regulated cell death pathways and should not be equated with ferroptosis per se.

3.1. Ferroptosis-related alterations in depression models and vulnerable brain regions

Evidence linking ferroptosis to MDD has been derived primarily from preclinical depression models, especially chronic stress-related paradigms. Among these, chronic unpredictable mild stress (CUMS (Tier II classical model)) remains the most frequently used model for investigating ferroptosis-associated molecular alterations in depressive-like states. Hippocampal proteomic analysis in CUMS mice has identified changes in proteins associated with regulated cell death and iron handling, including ferroptosis-related alterations such as FTL [103]. In addition, studies using CUMS, corticosterone exposure, lipopolysaccharide challenge, and disease-comorbidity models have reported changes in iron deposition, Fe²⁺ levels, malondialdehyde, glutathione, GPX4, SLC7A11, ACSL4, PTGS2/COX-2, and TFR1 [23]. These findings suggest that ferroptosis-related signatures are repeatedly detectable across experimental depressive-like states, although most evidence remains based on molecular markers rather than direct visualization of ferroptotic cell death.

The hippocampus is the most commonly studied brain region in this field. This emphasis is biologically reasonable because the hippocampus is highly sensitive to chronic stress and is closely involved in mood regulation, neurogenesis, and cognitive-emotional processing [104]. In several depression models, hippocampal ferroptosis-related changes have been associated with depressive-like behaviors, including reduced antioxidant defense, increased iron accumulation, enhanced lipid peroxidation, and altered expression of GPX4 or SLC7A11 [23]. For example, sestrin 2 (SESN2) was reported to attenuate depressive-like behaviors and neuroinflammation in CUMS mice while reducing iron deposition, Fe²⁺ content, lipid peroxidation, and ferroptosis-related protein abnormalities [105]. These observations indicate that hippocampal ferroptosis may represent a convergent molecular response to chronic stress and inflammatory activation.

Beyond the hippocampus, other mood-related regions have also been implicated, although the evidence is less systematic. The prefrontal cortex, hypothalamus, and other limbic or stress-responsive regions have been examined in selected models, particularly in studies focusing on metabolic stress, gut-derived inflammation, post-stroke depression (Tier III comorbidity model), traumatic brain injury (TBI)-associated depression (Tier III comorbidity model), or diabetes-associated depressive-like behaviors [43,106]. In these contexts, ferroptosis-related alterations are often accompanied by mitochondrial dysfunction, inflammatory signaling, or disrupted metabolic homeostasis, suggesting that ferroptosis may operate as part of a broader stress-responsive pathological network rather than as an isolated event within one brain region. A recent review also summarizes multiple ferroptosis-related signaling changes in depression models, including GPX4, Nrf2, TFR1, ACSL4, SLC7A11, and inflammatory mediators, supporting this network-level interpretation [3].

A systematic survey reveals that the current evidence is heavily hippocampus-weighted. In the prefrontal cortex (PFC), stress-induced ferroptosis-related changes in iron handling, lipid peroxidation, and GPX4 expression have been reported, though fewer studies directly compare PFC and hippocampal ferroptosis markers in the same model. The hypothalamus participates in stress-axis regulation and iron-sensing, yet dedicated ferroptosis studies in hypothalamic nuclei remain scarce. The habenula, thalamus, and striatum have been implicated in depression circuitry, but their ferroptosis-related alterations are only beginning to be explored. Therefore, while the section title invokes “vulnerable brain regions” in the plural, the available data justify primarily hippocampal claims, and findings in other regions should be considered preliminary.

Nevertheless, the current evidence should be interpreted cautiously. Many studies identify ferroptosis primarily through a limited panel of markers, such as decreased GPX4 or SLC7A11, increased malondialdehyde (MDA)—a nonspecific end-product of lipid peroxidation—

3.2. Neuronal and neural progenitor ferroptosis: implications for neuroplasticity

Neurons are among the most biologically plausible cellular targets of ferroptosis in MDD-related pathology. Their high oxygen consumption, abundant mitochondria, enrichment in polyunsaturated membrane lipids, and dependence on finely regulated redox balance make them intrinsically vulnerable to iron-dependent lipid peroxidation [107]. In mood-related brain regions, especially the hippocampus and prefrontal cortex, even sublethal oxidative membrane injury may interfere with synaptic transmission, dendritic remodeling, and neuroplasticity before overt neuronal loss becomes evident. Therefore, neuronal ferroptosis may contribute to depression not only by inducing cell death, but also by disrupting neuronal function within circuits that regulate emotion, cognition, and stress adaptation [107].

Preclinical studies have provided several lines of evidence supporting this possibility. In CUMS-induced depressive-like models (Tier II), ferroptosis inhibition with ferrostatin-1 alleviated behavioral abnormalities and promoted neuronal growth, suggesting that ferroptosis-related injury may participate in stress-induced neuronal dysfunction [40]. Mechanistically, this study further identified tsRNA-3029b as a ferroptosis-associated small RNA: in corticosterone-induced neuronal injury models, silencing tsRNA-3029b reduced ferroptosis and facilitated neuronal regeneration, accompanied by restoration of ferroptosis-related markers such as SLC7A11 and GPX4. These findings connect chronic stress, neuronal ferroptotic vulnerability, and impaired regenerative capacity, providing a molecular entry point for understanding how ferroptosis may affect neuronal plasticity in depression [40].

Neural stem/progenitor cells (NSPCs) represent another important neuronal-lineage population in this context. Hippocampal NSPCs are highly sensitive to glucocorticoid exposure and are closely linked to adult neurogenesis, a process frequently implicated in stress susceptibility and antidepressant response. Recent studies indicate that NLR family pyrin domain-containing 6 (NLRP6) helps maintain NSPC homeostasis under stress conditions [108]. NLRP6 deficiency, including neural stem cell–conditional knockout, increases susceptibility to stress-induced depressive-like behaviors, while a subsequent study reported that NLRP6 protects NSPCs from corticosterone-induced ferroptosis by regulating retinoic acid-inducible gene I/mitochondrial antiviral-signaling protein (RIG-I/MAVS)-mediated mitophagy and mitochondrial homeostasis [82]. These findings suggest that ferroptosis may impair depression-related neurogenesis not only through direct neuronal injury, but also by damaging progenitor populations required for hippocampal plasticity. Mechanistically, the emerging causal sequence is: NLRP6 deficiency → impaired RIG-I/MAVS signaling → impaired mitophagy and mitochondrial dysfunction → ferroptosis in NSPCs → loss of adult hippocampal neurogenesis. This pathway illustrates how innate immune signaling, mitochondrial quality control, ferroptosis, and impaired neuroplasticity can be organized into a single coherent mechanism.

The mechanistic relevance of neuronal ferroptosis is also supported by studies focusing on lipid peroxidation and GPX4-centered protection in the hippocampus. Traditional formula and natural compound studies have reported that improvement of depressive-like behaviors is accompanied by restoration of hippocampal ferroptosis-related pathways, including PEBP1/GPX4, Nrf2/GPX4, SLC7A11/GPX4, or suppression of lipid peroxidation markers [23,25]. Although many of these interventions are not neuron-specific, their consistent use of hippocampal tissue, neuronal injury markers, and behavioral rescue supports the concept that ferroptosis-related oxidative membrane damage may participate in the loss of neuronal integrity and plasticity in MDD-related models.

However, the current evidence for neuronal ferroptosis in MDD still has important limitations. Many studies infer neuronal ferroptosis from whole hippocampal or prefrontal tissue changes, such as decreased GPX4 or SLC7A11, increased MDA, Fe²⁺ accumulation, or altered ACSL4/PTGS2 expression. These markers are compatible with ferroptosis but do not always establish that neurons are the specific dying cell population. In vitro studies using primary neurons, PC12 cells, or corticosterone-induced neuronal injury models provide more direct cellular evidence, but they cannot fully reproduce the multicellular brain environment of MDD. Therefore, neuronal ferroptosis should currently be interpreted as a strongly suggested but still incompletely resolved mechanism linking chronic stress to impaired neuroplasticity. Future studies using cell-type-specific genetic manipulation, ferroptosis reporters, lipid peroxide imaging, and spatial transcriptomic approaches will be needed to determine where, when, and to what extent neuronal ferroptosis contributes to depressive pathology. As an illustrative example of emerging delivery strategies not yet tested in MDD models, mesenchymal stem cell-derived exosomes have been proposed as ferroptosis-targeted therapeutic vehicles [109], highlighting a translational direction that this review identifies as a promising direction for future depression research.

3.3. Microglial ferroptosis and neuroinflammatory amplification

Microglia are central immune-responsive cells in the brain and have long been implicated in the inflammatory component of MDD. Under chronic stress, infection-related immune activation, or systemic inflammatory challenge, microglia can shift toward a pro-inflammatory state characterized by increased production of cytokines and activation of pathways such as nuclear factor-κB (NF-κB) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome [110]. These inflammatory pathways are closely connected with oxidative stress and redox imbalance, which also represent key conditions favoring ferroptotic vulnerability [111]. In this setting, microglia provide an important cellular interface between neuroinflammation and ferroptosis rather than serving only as passive inflammatory markers in depressive pathology.

Compared with neuronal ferroptosis, direct evidence for microglial ferroptosis in depression remains more limited, but several recent studies have begun to define this link. A representative example is the study of cynaroside in a CUMS model (Tier II), which reported that cynaroside improved depressive-like behavior while suppressing microglial inflammation and ferroptosis through the interferon regulatory factor 1 (IRF1)/SLC7A11/GPX4 signaling pathway [7]. This study is valuable because it does not merely measure whole-hippocampus ferroptosis markers; it places ferroptosis within a microglial inflammatory context and connects the therapeutic effect to restoration of the anti-ferroptotic SLC7A11/GPX4 axis.

The biological relevance of this relationship lies in the bidirectional interaction between ferroptosis and inflammation. On one side, inflammatory activation can promote oxidative stress, alter iron handling, and increase lipid peroxidation, thereby creating conditions that favor ferroptosis. On the other side, ferroptotic injury may release oxidized lipids and damage-associated signals that further stimulate inflammatory responses [112]. In microglia, this interaction is particularly important because these cells are both sensors and amplifiers of brain inflammation. Once microglial redox homeostasis is disrupted, ferroptosis-related lipid damage may reinforce inflammatory signaling, while inflammatory mediators may further suppress antioxidant defenses such as the SLC7A11/GPX4 axis.

Several depression-related studies indirectly support this inflammatory–ferroptotic coupling. In CUMS or inflammation-associated models (Tier II), therapeutic interventions that improve depressive-like behaviors frequently reduce microglial activation markers, pro-inflammatory cytokines, lipid peroxidation, and ferroptosis-related abnormalities [105]. However, many of these studies still rely on tissue-level detection of GPX4, SLC7A11, ACSL4, PTGS2/COX-2, iron, or MDA, together with general inflammatory indicators such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), NF-κB, or NLRP3 [113]. These findings support an association between microglial inflammation and ferroptosis-related stress, but they do not always prove that ferroptosis occurs specifically within microglia.

A cautious interpretation is therefore needed. Microglia are likely to participate in depression-associated ferroptotic pathology in at least two ways: as cells that may themselves undergo ferroptosis under sustained inflammatory and oxidative stress, and as inflammatory amplifiers that promote ferroptotic vulnerability in neighboring neurons or glial cells. This distinction matters because the therapeutic implications are different. If microglia are the direct ferroptotic targets, then restoring microglial SLC7A11/GPX4 signaling or limiting microglial iron-lipid oxidative stress may be central. If microglia primarily act as upstream inflammatory drivers, then inhibiting NF-κB/NLRP3 activation, reducing cytokine release, or blocking inflammatory iron redistribution may be equally important. The two possibilities—microglial ferroptosis itself versus microglia-driven inflammatory amplification of ferroptosis in neighboring cells—are not mutually exclusive and remain difficult to separate with currently available data.

At the current stage, the microglial evidence is promising but still developing. The strongest available studies begin to move beyond whole-tissue ferroptosis markers toward cell-associated mechanisms, but future work needs more direct confirmation using microglia-specific genetic tools, lipid peroxide imaging, single-cell or spatial transcriptomics, and ferroptosis rescue experiments.

3.4. Astrocytic ferroptosis and glutamate homeostasis: emerging evidence

Astrocytes are essential regulators of the brain microenvironment and are closely involved in several processes relevant to MDD, including neurotransmitter cycling, antioxidant defense, metabolic support, inflammatory modulation, and synaptic plasticity. Unlike neurons, astrocytes are not only exposed to oxidative and metabolic stress but also actively buffer extracellular glutamate, provide metabolic substrates to neurons, and contribute to redox homeostasis through glutathione-related pathways [114]. These functions make astrocytes particularly important when considering ferroptosis in depression, because impairment of astrocytic antioxidant capacity or glutamate clearance can indirectly reshape neuronal excitability and circuit stability. Recent reviews of astrocyte dysfunction in depression have also emphasized their roles in synaptic regulation, neurotransmitter recycling, metabolic support, and neurovascular integrity [115].

Direct evidence connecting astrocytic ferroptosis with depressive-like behavior has only recently begun to emerge. A particularly important study identified poly(rC)-binding protein 1 (PCBP1) as a key regulator of astrocytic ferroptosis in the ventral hippocampus. PCBP1 functions as an intracellular iron chaperone, and its reduction in astrocytes increased ferroptotic vulnerability under stress conditions [116]. In this model, astrocytic ferroptosis was not presented merely as isolated glial injury; it was linked to impaired glutamate clearance and altered glutamatergic neuronal activity, providing a cellular route through which astrocyte dysfunction may influence depressive-like behaviors. Pharmacological inhibition of ferroptosis or astrocyte-specific restoration of PCBP1 counteracted stress-induced depressive-like phenotypes (Tier II), which makes this study one of the more direct pieces of evidence for astrocyte-centered ferroptosis in depression [116].

The relevance of astrocytic ferroptosis is closely tied to glutamate homeostasis. Astrocytes normally remove extracellular glutamate through excitatory amino acid transporters and convert glutamate into glutamine as part of the glutamate–glutamine cycle. When astrocytes are injured or metabolically compromised, extracellular glutamate can accumulate, increasing excitatory pressure on neurons and disturbing synaptic signaling [117]. In a ferroptosis context, this relationship is especially meaningful because glutamate metabolism is also connected to System Xc⁻, the cystine/glutamate antiporter that supports cysteine uptake and glutathione synthesis [118]. Thus, astrocytic dysfunction may influence depression-related ferroptosis through two related routes: reduced antioxidant support and impaired control of glutamatergic transmission. Specifically, astrocytes clear synaptic glutamate primarily through EAAT1 (GLAST) and EAAT2 (GLT-1), and their capacity to sustain the glutamate–glutamine cycle is essential for both glutamatergic homeostasis and neuronal antioxidant defense. Impairment of these transporters or of astrocyte-derived glutathione support would simultaneously compromise glutamate buffering and ferroptosis defense, linking two core pathophysiological themes in MDD.

Astrocytes may also shape ferroptosis susceptibility in neighboring cells. They participate in brain antioxidant defense by supporting glutathione metabolism and supplying neurons with metabolic substrates required for redox balance. If astrocytes undergo ferroptotic stress, their capacity to maintain the extracellular and metabolic environment may decline before widespread cell death becomes detectable [119]. This point is important for MDD because depressive pathology is unlikely to depend only on overt neuronal loss; more subtle changes in astrocyte-mediated support may be sufficient to affect synaptic function, neuroplasticity, and stress adaptation. In this sense, astrocytic ferroptosis may operate less as a terminal event and more as a mechanism that destabilizes neuron–glia communication.

Compared with neuronal and microglial evidence, the astrocytic ferroptosis literature in depression is still limited. Most available studies on ferroptosis in MDD-related models rely on whole hippocampal or cortical tissue, making it difficult to assign changes in GPX4, SLC7A11, ACSL4, iron, or lipid peroxidation to astrocytes specifically. The PCBP1-centered work provides a useful direction because it combines astrocyte specificity with behavioral and glutamatergic outcomes, but similar studies remain scarce.

3.5. Other emerging cellular and systemic contributors

Beyond neurons, microglia, and astrocytes, several additional cellular and systemic factors may contribute to ferroptosis-related pathology in MDD, although the available evidence remains limited. Oligodendrocyte-lineage cells are of potential interest because of their lipid-rich membranes, iron-dependent role in myelination, and vulnerability to oxidative injury. However, direct evidence linking oligodendrocyte ferroptosis to MDD is still scarce, and current support is mainly extrapolated from broader central nervous system disorders or stress-related models involving myelin and lipid peroxidation abnormalities [120]. Oligodendrocytes and their precursors are iron-rich and depend on lipid metabolism for myelin maintenance, making them plausible ferroptosis targets whose dysfunction could disrupt axonal integrity and network-level communication in MDD-related circuits.

Blood–brain barrier (BBB)-related mechanisms and peripheral signals may also participate in this process. Depression is frequently associated with systemic inflammation and altered brain–periphery communication, both of which may influence BBB integrity and central redox balance. Although ferroptosis of brain microvascular endothelial cells has been reported in other neurological injury models, its direct contribution to MDD remains insufficiently defined [121]. Similarly, gut-derived inflammatory and metabolic signals, including short-chain fatty acids and indole metabolites, have been linked to neuroinflammation, oxidative stress, and ferroptosis-related regulation in depression-related models, but most studies have not yet resolved the specific cellular targets involved [122]. Exosome-mediated communication further illustrates the brain-periphery crosstalk axis. Bao et al. recently reviewed how exosomes modulate ferroptosis, regulate brain-periphery communication, and offer BBB-crossing delivery strategies—themes that are directly relevant to the systemic contributors discussed in this section [123]. Ferroptotic injury to brain microvascular endothelial cells could disrupt BBB integrity, while gut-derived inflammatory signals and microbial metabolites may reach the CNS via a compromised BBB and amplify systemic-to-central ferroptosis crosstalk. These pathways remain underexplored in depression and represent important directions for future work.

Thus, oligodendrocytes, BBB-associated cells, gut-derived metabolites, and peripheral immune–metabolic factors should currently be regarded as emerging contributors rather than established ferroptotic drivers of MDD. Most of the cell-type inferences discussed in Sections 3.2–3.4 derive from whole-tissue or mixed-cellular homogenates (hippocampus, cortex, hypothalamus), which cannot resolve whether molecular changes originate from neurons, glia, endothelia, or infiltrating peripheral cells. Future studies incorporating cell-type-specific genetic manipulation, ferroptosis reporters, and single-cell resolution techniques will be necessary to move beyond tissue-level association.

The integrated pathological chain from chronic stress to depressive-like behavior is summarized in Fig. 2.

4. Therapeutic strategies targeting ferroptosis in MDD

Interventions are organized below by source class rather than by mechanism to reflect how they enter the literature, and each category is discussed with explicit attention to the level of evidence (marker-based vs. rescue-validated vs. clinically tested).

Before reviewing the therapeutic evidence, we note that iron-related changes throughout this section are characterized as iron dyshomeostasis rather than as a simple ‘iron accumulation’ phenotype. Interventions may affect labile iron pools, iron-sensing pathways, or iron-dependent lipid peroxidation without necessarily reducing total tissue iron content.

Throughout §4, “ferroptosis” as used for individual studies reflects the authors’ marker-based interpretation unless rescue or genetic validation was performed.

4.1. Natural products and bioactive compounds

Natural products constitute the largest group of ferroptosis-targeted interventions investigated in preclinical models of MDD and depression-related conditions. Their appeal does not lie in a single molecular target, but in their ability to simultaneously regulate oxidative stress, inflammatory signaling, iron handling, lipid peroxidation, and antioxidant defense. In the available literature, most natural compounds have been tested in animal models such as CUMS, chronic restraint stress (CRS), corticosterone (CORT)-induced injury, post-stroke depression, perimenopausal depression, chronic pain comorbidity, or disease-associated depressive-like states. Although these studies remain largely preclinical, they provide a useful pharmacological map of the ferroptosis-related pathways that may be therapeutically modifiable in MDD.

Flavonoids and polyphenolic compounds are the most frequently represented subgroup. Quercetin has been studied across several depression-related contexts. In a breast cancer-related depression model, quercetin inhibited neuronal ferroptosis and promoted immune responses by targeting the lipid metabolism-related gene prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2) [4]. In perimenopausal depression models, quercetin was further reported to reduce ferroptosis-associated mitochondrial damage in the hypothalamus by modulating an acetyl-H3K9-mediated ferroptosis pathway, with increased GPX4 and SLC7A11 expression and reduced endoplasmic reticulum (ER) stress markers such as inositol-requiring enzyme 1α (IRE1α), X-box binding protein 1 (XBP1), and glucose-regulated protein 78 (GRP78) [5]. Metabolomic studies also linked quercetin to improved hippocampal or prefrontal cortical metabolic disturbance and reduced ferroptosis in perimenopausal depression models [6]. These findings make quercetin one of the more repeatedly studied natural compounds in this field, with mechanisms spanning PTGS2-dependent lipid metabolism, epigenetic regulation, ER stress, and the SLC7A11/GPX4 antioxidant axis.

Other flavonoid-like compounds also intersect with inflammation–ferroptosis coupling. Cynaroside improved depressive-like behavior in CUMS mice by suppressing microglial inflammation and ferroptosis through the interferon regulatory factor 1 (IRF1)/SLC7A11/GPX4 pathway; transcriptomic validation further connected cynaroside with reduced inflammatory polarization, lipid peroxidation, and ferroptosis in BV-2 microglia [7]. Sinensetin, another natural flavonoid, was reported to attenuate post-stroke depression through dual modulation of the Toll-like receptor 4 (TLR4)/NF-κB inflammatory axis and the Nrf2/GPX4 ferroptosis-protective pathway [8]. Baicalin has been examined in atherosclerosis-associated depression, where metagenomic and lipidomic analyses suggested that it improved depressive behavior by modulating gut microbiota and lipid metabolism while inhibiting neuronal ferroptosis [9]. Together, these studies suggest that flavonoid compounds often act at the intersection of NF-κB-driven inflammation, Nrf2/GPX4-mediated antioxidant defense, and lipid peroxidation control.

Polyphenols and phenolic acids provide another important set of natural anti-ferroptotic candidates. Resveratrol alleviated depression-like behaviors by inhibiting ferroptosis through the protein kinase B (AKT)/Nrf2 pathway; in PC12 cells, erastin-induced ferroptosis and suppression of AKT/Nrf2 signaling were counteracted by resveratrol, whereas pathway blockade with LY294002 or ML385 weakened its protective effect [10]. Gallic acid improved comorbid chronic pain and depression-like behaviors by inhibiting P2X7 receptor-mediated ferroptosis in the spinal cord, linking purinergic signaling to ferroptotic neuroinflammatory injury in a pain–depression comorbidity model [11]. Pellitorine was recently reported to protect against CRS-induced cognitive deficits by reducing neuroinflammation and ferroptosis, although its depression-specific evidence is less developed than that of quercetin or resveratrol [12].

Saponins, glycosides, and terpenoid-like compounds have also been repeatedly investigated. Saikosaponin B2 (SSB2) ameliorated depression-induced microglial activation by inhibiting ferroptosis-mediated neuroinflammation and endoplasmic reticulum stress. Mechanistically, SSB2 reduced lipid peroxidation and intracellular Fe²⁺, maintained calcium homeostasis, and acted through TLR4/NF-κB signaling in a GPX4-dependent manner [13]. Asiaticoside attenuated CRS-induced hippocampal CA1 neuronal ferroptosis via activation of the brain-derived neurotrophic factor (BDNF)/Nrf2/GPX4 pathway, with additional evidence of increased SLC7A11, preserved mitochondrial morphology, and reduced ferroptosis markers such as transferrin receptor and ferritin-related abnormalities in the CA1 region [14]. Gypenosides attenuated CORT-induced ferroptosis in PC12 cells by inhibiting the TNF-α/NF-κB pathway, providing in vitro support for the anti-inflammatory regulation of ferroptosis under glucocorticoid stress [15]. Atractylodin, a sesquiterpene compound, alleviated depressive-like behaviors in CUMS rats and improved hippocampal neuronal changes; multi-omics analysis connected its effects with increased GPX4, SLC7A11, BDNF, and Nrf2, together with reduced IL-1β, TNF-α, MDA, and ROS [16].

Several natural agents appear to act through more specialized cellular or circuit mechanisms. Hydroxysafflor yellow A (HSYA) attenuated CUMS-induced depressive-like behavior by reducing hippocampal microglial activation and ferroptosis, with involvement of sirtuin 1 (SIRT1)/Nrf2/NF-κB signaling [17]. Bufotenidine was reported to attenuate astrocyte ferroptosis in depressive-like behaviors by targeting the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) subunit glutamate ionotropic receptor AMPA-type subunit 1 (GluA1), thereby reducing neuronal lipid synthesis and linking neuron–astrocyte metabolic coupling to ferroptosis regulation [18]. Spinosin, derived from Ziziphus jujuba, has been connected to the coordination of synaptic plasticity and ferroptosis through protein tyrosine phosphatase 1B (PTP1B), suggesting that anti-ferroptotic effects may interact with synaptic remodeling rather than simply preventing terminal cell death [19].

Polysaccharide, glycopeptide, and animal-derived preparations broaden the scope of natural interventions beyond small molecules. Lycium barbarum glycopeptide (LBGP) prevented stress-induced anxiety-like phenotypes by regulating oxidative stress and ferroptosis in the medial prefrontal cortex, highlighting the relevance of prefrontal redox–ferroptotic vulnerability in stress-related affective behaviors [20]. Atractylodes macrocephala Koidz. polysaccharide (AP) alleviated chemotherapy-induced depression-like behaviors through the gut–brain axis and was associated with reduced intestinal ferroptosis, improved intestinal barrier injury, and altered gut microbiota and metabolites [21]. Seahorse extract attenuated DSS-induced depression-like behavior by suppressing neuroinflammation and ferroptosis; molecularly, it increased pNrf2 and downstream HO-1, GPX4, and SLC7A11, thereby counteracting DSS-induced hippocampal ferroptosis [22].

Overall, natural products targeting ferroptosis in MDD-related models can be organized around several recurring molecular nodes: restoration of the SLC7A11/GPX4 axis, activation of Nrf2-centered antioxidant signaling, suppression of NF-κB/NLRP3-related inflammation, reduction of PTGS2/ACSL4-associated lipid peroxidation, modulation of iron-related markers such as Fe²⁺ or TFR1, and protection of mitochondrial or synaptic integrity. Despite the breadth of positive reports, several important caveats apply. Most natural-product studies rely on a single dose and route; active-compound standardization, blood–brain barrier penetration, and pharmacokinetic data are rarely available. Negative or null findings are seldom reported, raising concern for publication bias. At the current stage, the natural-product evidence for ferroptosis-targeted antidepressant effects should be regarded as hypothesis-generating rather than as established clinical evidence, pending rigorous dose-response, pharmacokinetic, and safety studies.

4.2. Traditional medicine formulas and traditional non-pharmacological interventions

Compared with isolated natural compounds, traditional medicine formulas represent multi-component interventions that may regulate ferroptosis through broader pharmacological networks. This feature is particularly relevant to MDD, where ferroptosis-related pathology is often accompanied by oxidative stress, neuroinflammation, mitochondrial dysfunction, glutamatergic disturbance, and impaired neuroplasticity. Current evidence suggests that several traditional formulas alleviate depressive-like phenotypes by acting on ferroptosis-related pathways, although most studies remain preclinical and use rodent models or cell-based validation systems.

Xiaoyaosan is one of the earliest and most frequently discussed formulas in this field. In CUMS mice, Xiaoyaosan alleviated depressive-like behavior while regulating hippocampal ferroptosis through the PEBP1/GPX4 pathway. Mechanistically, this study linked CUMS-induced depressive-like behavior to hippocampal iron dyshomeostasis (including increased iron accumulation)Xiaoyaosan partially reversed these abnormalities [23]. The importance of this work lies in its relatively clear positioning of ferroptosis within the hippocampal pathology of chronic stress rather than treating ferroptosis as a nonspecific oxidative stress marker. In addition to this direct ferroptosis-related evidence, other systems-level studies have explored Xiaoyaosan in depression-related comorbid contexts such as metabolic dysfunction, but the PEBP1/GPX4 axis currently remains the most relevant molecular link between Xiaoyaosan and ferroptosis-oriented antidepressant action [23].

Several formulas have been investigated in post-stroke depression (PSD), a condition in which ischemic injury, neuroinflammation, oxidative stress, and depressive-like behavior intersect. Di-Huang-Yin-Zi (DHYZ) improved PSD-related outcomes through regulation of the p53/SLC7A11 pathway, indicating that restoration of System Xc⁻-associated anti-ferroptotic defense may contribute to its therapeutic effect [24]. Yi-Nao-Jie-Yu prescription (YNJY) was reported to relieve PSD by mitigating hippocampal neuronal ferroptosis through activation of the Nrf2/GPX4/SLC7A11 pathway; mechanistic validation further showed that Nrf2 inhibition with ML385 or Nrf2 silencing weakened the anti-ferroptotic effect of YNJY in erastin-treated hippocampal neurons [25]. These studies place PSD-related formulas within two major ferroptosis-regulatory axes: p53/SLC7A11-mediated cystine transport control and Nrf2-driven antioxidant restoration.

Other traditional formulas extend the therapeutic discussion beyond classical CUMS models. Kai-Xin-San (KXS) alleviated adriamycin-induced depression-like behaviors in mice by reducing ferroptosis in the prefrontal cortex, suggesting that ferroptosis may also participate in chemotherapy-associated affective dysfunction [26]. Bushen Shugan Huayu formula improved depressive-like behavior in perimenopausal mice by modulating neuronal ferroptosis through the G protein-coupled estrogen receptor 1 (GPER1)/Nrf2 pathway, which is particularly relevant because perimenopausal depression involves endocrine fluctuation, oxidative stress, and altered neuronal resilience [27]. These studies support the idea that traditional formulas may target ferroptosis in disease-specific depressive contexts, including cancer therapy-associated depression and hormone-transition-related depression.

Some formulas appear to act outside the central nervous system while still being relevant to depression-related ferroptosis networks. Baihe Dihuang Danshen decoction (BDDSD) was studied in depression-induced rats with myocardial ischemia–reperfusion injury, where it alleviated myocardial injury by inhibiting ferroptosis. This evidence should be interpreted differently from hippocampal or prefrontal ferroptosis studies: it does not primarily demonstrate direct anti-ferroptotic action in the depressive brain, but it supports a systemic view in which depression may aggravate peripheral organ injury through ferroptosis-sensitive pathways [28]. For a review centered on MDD, BDDSD is therefore better positioned as evidence for depression-associated systemic ferroptotic vulnerability rather than as a core brain-targeted antidepressant mechanism.

Traditional non-pharmacological interventions provide another important subgroup. Manual acupuncture has been tested in CUMS-induced depressive-like rats, with fluoxetine and acupoint catgut embedding used as comparative interventions. Acupuncture improved depressive-like behaviors, reversed oxidative stress indices including MDA, superoxide dismutase (SOD), GSH, GSH-Px, and total antioxidant capacity (T-AOC), reduced inflammatory mediators such as IL-1β, IL-6, and TNF-α, and restored hippocampal SIRT1/Nrf2/heme oxygenase-1 (HO-1)/GPX4 signaling [29]. It also reduced hippocampal microglial and astrocytic activation [29]. In this context, acupoint catgut embedding is best mentioned as a comparator within the acupuncture study rather than as a fully established independent ferroptosis-targeting therapy, unless additional ferroptosis-specific evidence is added later.

Electroacupuncture (EA) has been examined across several depression-related models. In PSD rats, EA alleviated depressive-like behavior and inhibited ferroptosis in prefrontal cortical neurons, with reductions in iron deposition and lipid peroxidation and improvement of mitochondrial injury [106]. In chronic inflammatory pain and depression comorbidity, EA was linked to inhibition of hippocampal neuronal ferroptosis through an Nrf2-mediated mechanism [30]. Another recent study reported that EA alleviated depression-like behavior after spinal cord injury through SIRT1/High mobility group box 1 (HMGB1) signaling axis–mediated ferroptosis, while work on early-life chronic sleep deprivation suggested that EA may regulate circadian autophagy-related ferroptosis in hippocampal neurons [31]. These models differ substantially, but they collectively place EA at the intersection of ferroptosis, neuroinflammation, mitochondrial protection, and circuit-level recovery.

A related acupuncture approach, “Shugan Tiaoshen” acupuncture, was reported to improve chronic inflammatory pain and depression comorbidity by inhibiting ferroptosis in hippocampal neurons [32]. This fits well with the broader pattern observed in EA studies, where the hippocampus appears as a recurrent target region and ferroptosis suppression is often accompanied by decreased lipid peroxidation and inflammatory stress. Because pain–depression comorbidity involves both affective and nociceptive circuits, this study also broadens the therapeutic context in which ferroptosis-targeted acupuncture may be relevant.

Finally, traditional pediatric massage (TPM) has been evaluated in adolescent rats exposed to CUMS. TPM enhanced resilience to CUMS and exerted antidepressant-like effects partly through activation of the insulin-like growth factor 1 (IGF-1)/Nrf2 pathway, maintenance of hippocampal function, and reduction of neuroinflammation [33]. Although the ferroptosis-specific evidence is less direct than in Xiaoyaosan, DHYZ, YNJY, or EA studies, the involvement of Nrf2-centered antioxidant signaling makes TPM relevant to the broader anti-ferroptotic therapeutic landscape. Its inclusion also highlights that traditional non-pharmacological interventions may regulate ferroptosis-related vulnerability indirectly through neurotrophic, antioxidant, and anti-inflammatory pathways.

Taken together, traditional formulas and non-pharmacological interventions appear to converge on several ferroptosis-related molecular modules: PEBP1/GPX4, p53/SLC7A11, Nrf2/GPX4/SLC7A11, SIRT1/Nrf2/HO-1/GPX4, GPER1/Nrf2, SIRT1/HMGB1, and IGF-1/Nrf2. Compared with single compounds, these interventions are harder to assign to one precise molecular target, but their repeated convergence on antioxidant defense, lipid peroxidation control, inflammatory suppression, and iron-dependent neuronal vulnerability supports their inclusion as a distinct therapeutic category in ferroptosis-oriented MDD research. Importantly, multi-target activity is not intrinsically advantageous: traditional formulas and acupuncture-related interventions face challenges in active-component definition, target specificity, batch-to-batch reproducibility, and mechanistic attribution. Therefore, their reported anti-ferroptotic effects should be interpreted cautiously pending more rigorous chemical standardization and target-engagement evidence.

4.3. Chemical agents, repurposed drugs, ferroptosis inhibitors, and biomedical interventions

Exercise-based interventions. Aerobic exercise has been shown to improve overall outcomes in metabolic-psychiatric comorbidity, with potential antioxidant, anti-inflammatory, and metabolic benefits. This work is cited here as support for an adjunctive metabolic intervention with plausible relevance to oxidative-stress and iron-handling pathways, not as direct evidence for ferroptosis-targeted MDD therapy. Controlled studies explicitly examining whether aerobic exercise modulates ferroptosis markers in MDD patients are currently lacking [124].

In addition to natural products and traditional medicine-related interventions, several chemical agents, repurposed drugs, ferroptosis inhibitors, and biomedical strategies have been investigated in MDD-related or depression-like models. Compared with natural compounds, these interventions often provide clearer pharmacological entry points for dissecting ferroptosis-related mechanisms, including antioxidant signaling, iron chelation, GPX4-dependent lipid peroxide detoxification, mitochondrial protection, and neuroinflammatory control. However, many of these studies remain model-specific, and only a subset directly examines MDD-like pathology rather than depression-associated comorbid conditions.

Edaravone, a free-radical scavenger used clinically in neurological disorders, is one of the more mechanistically defined pharmacological agents in this field. In chronic social defeat stress models, edaravone ameliorated depressive- and anxiety-like behaviors through activation of the SIRT1/Nrf2/HO-1/GPX4 pathway [34]. Mechanistic validation showed that inhibition of Nrf2 with ML385 weakened the protective effect of edaravone, and GPX4 knockdown abolished its behavioral efficacy, supporting a relatively direct link between GPX4-mediated ferroptosis suppression and antidepressant-like activity [34]. This places edaravone within an antioxidant–anti-ferroptotic framework rather than merely as a nonspecific ROS scavenger.

Melatonin has also been studied as a pharmacological modulator of ferroptosis in inflammatory depression models. In lipopolysaccharide (LPS)-induced depressive-like mice, melatonin reduced ferroptosis-associated oxidative injury by regulating an RNA methylation-related sirtuin 6/Nrf2/HO-1 pathway. Reported changes included decreased ROS, MDA, Fe²⁺, and ACSL4, together with increased SOD, GSH, GPX4, and Ferroptosis suppressor protein 1 (FSP1), indicating that melatonin may act through both GPX4-dependent and GPX4-parallel antioxidant systems [35]. Because LPS models emphasize inflammation-driven depressive-like behavior, melatonin also provides a useful example of how anti-inflammatory and anti-ferroptotic effects may overlap in depression-related pathology.

Several repurposed drugs have been explored in disease-associated depressive-like conditions. Nicorandil, a clinically used antianginal drug with ATP-sensitive potassium channel-opening and nitric oxide-donor properties, was reported to alleviate depressive-like behavior after TBI by suppressing hippocampal ferroptosis through the SLC7A11/GPX4 axis [36]. Although this model is not classical MDD, it is relevant to post-injury depressive phenotypes and suggests that modulation of mitochondrial excitability, vascular signaling, and anti-ferroptotic defense may intersect in TBI-associated affective dysfunction [36]. Rebamipide, originally used as a gastroprotective agent, has recently been repurposed in a letrozole-induced depressive-like model in female rats, where it was linked to SIRT1/Forkhead box O1 (FoxO1)/Wnt/β-catenin signaling and ferroptosis-related protection [37]. These studies broaden ferroptosis-targeted antidepressant research beyond conventional psychotropic drugs, but their disease-context specificity should be clearly acknowledged.

Agents used in neuropsychiatric or procedural contexts have also been connected with ferroptosis regulation. Ketamine, well known for its rapid antidepressant effects, was reported to improve chronic restraint stress-induced depressive-like behavior through modulation of neuroplasticity, autophagy, and ferroptosis in the habenular nucleus [38]. This study is notable because it links ferroptosis with a circuit-relevant brain region implicated in aversive processing and rapid antidepressant response, rather than focusing only on hippocampal ferroptosis markers. Etomidate, used as an anesthetic agent in electroconvulsive therapy (ECT)-related contexts, enhanced the antidepressant effect of ECT by suppressing hippocampal neuronal ferroptosis through upregulation of BDNF/Nrf2 signaling [39]. Together, ketamine and etomidate suggest that ferroptosis modulation may intersect with established rapid-acting or procedural antidepressant strategies, although these links remain early and require further validation.

More targeted experimental approaches include ferroptosis inhibitors, iron chelators, and nanomedicine-based delivery systems. Ferrostatin-1 (Fer-1), a classical ferroptosis inhibitor, reduced depressive-like behavior in CUMS mice and promoted neuronal growth; in CORT-treated neuronal models, ferroptosis-related injury was accompanied by ROS accumulation and decreased SLC7A11 and GPX4, while Fer-1 helped identify tsRNA-3029b as a ferroptosis-associated regulatory molecule [40]. Deferoxamine, an iron chelator, has been used as a mechanistic rescue agent in environmental exposure models, including realistic nanoplastic-induced depressive-like behaviors, where mitochondrial iron overload, ferritinophagy, lipid peroxidation, and dysregulated ferroptosis markers were implicated [41].

Nanomedicine-based strategies have begun to appear as well. GLX351322-loaded nanoparticles (GLX-NPs) alleviated chronic stress-induced depressive-like behaviors by inhibiting neuronal ferroptosis and oxidative stress. Mechanistically, this study connected the therapeutic effect to modulation of the NOX4/Nrf2/HO-1/GPX4 pathway, suggesting that nanoparticle delivery may improve the pharmacological targeting of oxidative stress–ferroptosis networks in stress-related depression [42]. Although this area is still very new, it provides a potential route for overcoming delivery limitations that often restrict antioxidant or anti-ferroptotic interventions in the central nervous system.

Other biomedical or small-molecule interventions further expand the therapeutic landscape. Hydrogen sulfide (H₂S), often administered experimentally through donors such as sodium hydrosulfide (NaHS), alleviated anxiety-like and depressive-like behaviors in type 1 diabetic mice by inhibiting inflammation and ferroptosis. This suggests that gaseous signaling molecules may influence mood-related phenotypes through metabolic and inflammatory ferroptosis pathways in systemic disease contexts [43]. l-Se-methylselenocysteine, a selenium-containing compound, was reported to alleviate iron deposition-induced anxiety- and depression-like behaviors in chronic renal failure rats receiving iron therapy through Nrf2/GPX4 activation [44]. Hyperbaric oxygen (HBO) protected against depressive behavior and cognitive impairment in a spinal cord injury rat model through regulation of Nrf2/GPX4 signaling [45]. These interventions are not classical antidepressant drugs, but they illustrate how ferroptosis-related affective phenotypes can emerge in systemic, injury-related, or metabolic disease settings.

Taken together, chemical agents and biomedical interventions targeting ferroptosis in depression-related models share several molecular modules, including SIRT1/Nrf2/HO-1/GPX4, SIRT6/Nrf2/HO-1, SLC7A11/GPX4, BDNF/Nrf2, NOX4/Nrf2/HO-1/GPX4, iron chelation, and GPX4-dependent lipid peroxide detoxification. Compared with natural products, these interventions often provide stronger mechanistic tools for testing ferroptosis causality, especially when combined with inhibitors, knockdown approaches, or rescue experiments. Their limitation is that many are studied in comorbidity or injury-associated depressive-like models rather than in primary MDD models, so their translational relevance to MDD should be interpreted cautiously. Direct evidence linking selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), lithium, or antipsychotic augmentation strategies to ferroptosis modulation in MDD is currently sparse. Although some of these agents influence oxidative stress, iron handling, or glutathione status in non-MDD contexts, whether clinically relevant antidepressant doses engage ferroptosis-specific pathways remains largely unexamined. This gap highlights an important direction for future research at the interface of clinical psychopharmacology and ferroptosis biology.

4.4. Nutrients, microbial metabolites, and gut–brain axis-related interventions

Nutrient-derived factors and microbial metabolites have recently attracted attention as modulators of ferroptosis-related depressive pathology. Compared with direct pharmacological inhibitors, these interventions are often positioned within a broader gut–brain or metabolic framework. Their relevance lies in the fact that depression is frequently accompanied by gut dysbiosis, systemic inflammation, altered intestinal barrier function, and disrupted microbial metabolism, all of which may influence central oxidative stress and ferroptosis susceptibility. In this context, nutrients and microbiota-derived metabolites may regulate ferroptosis indirectly by reshaping peripheral inflammation, intestinal permeability, metabolic signaling, and brain redox homeostasis.

Many interventions discussed in this section, particularly those with low oral bioavailability or limited blood–brain barrier penetration, are likely to exert their anti-ferroptotic effects at least in part through gut-microbiome remodeling (e.g., restoration of short-chain fatty acid (SCFA)-producing bacteria, reduction of intestinal permeability, and systemic anti-inflammatory effects), rather than through direct neuronal engagement. Conversely, interventions with documented brain penetration or those tested in direct neuronal culture systems may act via both routes. This dual mechanistic pathway should be kept in mind when interpreting therapeutic claims in this section.

Short-chain fatty acids (SCFAs) are the most representative microbial metabolites in this category. Butyric acid and valeric acid were reported to attenuate stress-induced depressive-like behaviors by suppressing hippocampal neuroinflammation and ferroptosis. In this study, stress exposure altered gut microbial composition and reduced SCFA-related metabolic support, whereas supplementation with butyric acid or valeric acid improved behavioral performance and reduced ferroptosis-related abnormalities in the hippocampus. Mechanistically, the protective effect was associated with decreased neuroinflammatory activation and restoration of ferroptosis-related indices, including iron accumulation, lipid peroxidation, and the SLC7A11/GPX4 antioxidant axis [46]. This provides a relatively direct example of gut-derived metabolites influencing hippocampal ferroptotic vulnerability under stress.

Butyrate has also been studied in acute stress-related depression-like behavior through a prefrontal cortex-centered gut–brain axis mechanism. Acute stress was reported to induce ferroptosis of prefrontal cortical neurons, accompanied by intestinal and blood–brain barrier impairment and systemic inflammatory responses. Butyrate intervention ameliorated depression-like behavioral changes, improved barrier injury, and reduced ferroptosis-related damage in the prefrontal cortex [122]. This study is useful because it does not restrict the effect of butyrate to local brain antioxidant regulation; instead, it places butyrate within a chain linking gut microbial metabolism, barrier integrity, systemic inflammation, and neuronal ferroptosis.

Tryptophan-derived microbial metabolites provide another route by which gut microbiota may influence ferroptosis-related pathology. Indole-3-propionic acid (IPA) was studied in the context of depression-aggravated myocardial ischemia/reperfusion injury along the brain–gut–heart axis. Depression was associated with altered gut microbiota and disturbed tryptophan metabolism, leading to reduced IPA levels. IPA supplementation alleviated myocardial injury by suppressing ferroptosis and oxidative stress through the Nrf2/System Xc⁻/GPX4 axis [47]. Although this evidence does not primarily demonstrate direct anti-ferroptotic action in the depressive brain, it is important for showing that depression-related microbial metabolic disruption can aggravate ferroptosis-sensitive peripheral injury. Therefore, IPA is better discussed as a systemic gut-derived protective metabolite rather than a conventional antidepressant candidate.

Polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), represent nutrient-derived lipid mediators with relevance to depression, neuroinflammation, and ferroptosis. In chronic sleep deprivation-induced depressive-like mice, DHA and EPA both alleviated depressive-like behaviors, but EPA showed a stronger effect. Mechanistically, this study linked the behavioral benefit to regulation of iron metabolism, suppression of oligodendrocyte lipid peroxidation, and inhibition of the LCN2/NLRP3 signaling axis [48]. In a pentylenetetrazol-induced kindling model with depression-like behavior, DHA and EPA also reduced neuroinflammation by promoting microglial M2 polarization and suppressing lipocalin 2 (LCN2)/NLRP3 inflammasome activity [49]. These findings suggest that ω-3 fatty acids may influence depression-related ferroptosis through myelin-associated lipid protection, iron metabolism, and neuroimmune regulation rather than through a single GPX4-centered mechanism.

Polysaccharide-based gut–brain axis interventions further broaden this category. AP alleviated pirarubicin chemotherapy-induced depression-like behaviors in breast cancer mice by regulating gut microbiota and microbial metabolism. The study reported that AP improved intestinal barrier damage, reduced intestinal ferroptosis, reshaped microbial composition, and restored depression-associated metabolic abnormalities. This evidence is particularly relevant because chemotherapy-induced depression-like behavior often involves intestinal injury, microbial dysbiosis, systemic inflammation, and central behavioral changes. Unlike compounds that directly modulate hippocampal GPX4 or SLC7A11, AP appears to act primarily through stabilization of the gut–brain axis and suppression of intestinal ferroptosis, thereby indirectly improving depressive-like phenotypes.

Taken together, nutrient- and microbiota-related interventions expand ferroptosis-targeted therapy beyond the brain-centered framework. SCFAs such as butyrate and valeric acid mainly connect gut microbial metabolism with hippocampal or prefrontal ferroptosis and neuroinflammation; IPA links depression-related microbial disruption to systemic ferroptosis-sensitive organ injury through the Nrf2/System Xc⁻/GPX4 axis; DHA and EPA act through lipid metabolism, oligodendrocyte protection, iron regulation, and LCN2/NLRP3-mediated neuroinflammation; and AP highlights intestinal ferroptosis and barrier dysfunction as upstream contributors to chemotherapy-associated depressive-like behavior. These studies are valuable because they place ferroptosis within a broader metabolic and gut–brain network, although most remain preclinical and still require clearer separation between direct central anti-ferroptotic effects and indirect peripheral metabolic regulation.

4.5. Mechanistic convergence of ferroptosis-targeted interventions

Although the interventions discussed above differ substantially in origin, composition, and experimental context, their reported mechanisms modulate a shared set of ferroptosis-related regulatory nodes. Natural compounds, traditional formulas, chemical agents, ferroptosis inhibitors, nutrients, and microbiota-derived metabolites have all been shown to modulate iron handling, lipid peroxidation, antioxidant defenses, inflammatory signaling, or mitochondrial homeostasis in MDD-related models. This convergence suggests that ferroptosis-targeted treatment should not be viewed as a single-pathway strategy, but rather as a therapeutic framework that intersects with several established pathological processes in depression.

The most frequently reported mechanism is restoration of the System Xc⁻/GSH/GPX4 axis. Many interventions increase SLC7A11, GSH, or GPX4, thereby enhancing the capacity to detoxify phospholipid hydroperoxides and restrain ferroptotic membrane damage. This axis is often regulated together with Nrf2-centered antioxidant signaling, including Nrf2/HO-1, SIRT1/Nrf2/HO-1/GPX4, SIRT6/Nrf2/HO-1, BDNF/Nrf2/GPX4, IGF-1/Nrf2, and GPER1/Nrf2 pathways. These findings indicate that many ferroptosis-targeted antidepressant-like interventions act less by directly blocking a single executor molecule and more by restoring the broader antioxidant network that maintains GPX4 activity and lipid peroxide detoxification.

A second shared therapeutic node involves regulation of iron metabolism and lipid peroxidation. Several interventions modulate iron metabolism by limiting the labile iron pool and reducing the expression of iron-related markers such as TFR1—reflecting iron dyshomeostasis rather than simply ‘clearing iron accumulation’—ferroptotic lipid damage. Some studies further implicate more specific lipid-peroxidation machinery, such as the PEBP1/GPX4 axis or pathways involving phospholipid oxidation. Together, these results suggest that effective interventions may act at both ends of the ferroptotic cascade: limiting upstream iron-dependent radical generation and reducing downstream accumulation of toxic oxidized phospholipids. However, MDA and bulk ROS are nonspecific oxidative-stress indices that overlap with non-ferroptotic pathways; stronger claims require more ferroptosis-selective readouts such as oxidized AA/AdA-PE species, C11-BODIPY 581/591 probe-based assays, 4-hydroxynonenal (4-HNE) adducts, and lipidomic profiling, ideally coupled with rescue experiments to strengthen the attribution to ferroptosis.

Inflammation-related pathways form another major point of convergence. Depression-related ferroptosis is frequently accompanied by activation of NF-κB, NLRP3, HMGB1, TLR4, IL-1β, IL-6, and TNF-α, particularly in models involving chronic stress, systemic inflammation, post-stroke depression, inflammatory pain, or gut-derived immune activation. Many interventions suppress these inflammatory pathways while simultaneously restoring SLC7A11/GPX4 or Nrf2/GPX4 signaling. This pattern supports a bidirectional relationship in which inflammatory activation promotes ferroptotic susceptibility through oxidative stress and altered iron–lipid metabolism, whereas ferroptosis-related lipid damage may further amplify inflammatory signaling. In therapeutic terms, anti-inflammatory and anti-ferroptotic effects are therefore difficult to separate and may represent coordinated components of the same protective response.

Mitochondrial and metabolic regulation also appears repeatedly across different intervention categories. Pathways involving SIRT1, BDNF, RIG-I/MAVS-mediated mitophagy, NOX4/Nrf2/HO-1/GPX4, and gut-derived metabolites suggest that ferroptosis-targeted therapies may improve depressive-like phenotypes by preserving mitochondrial function, limiting ROS production, and maintaining energy and redox homeostasis. Nutrients and microbial metabolites further extend this mechanism beyond the brain, linking intestinal barrier integrity, gut microbiota composition, short-chain fatty acids, tryptophan-derived metabolites, systemic inflammation, and central ferroptosis-sensitive injury. This broader metabolic perspective is particularly important because MDD is not confined to the brain, and ferroptosis-related vulnerability may be shaped by peripheral immune and metabolic states.

Overall, the therapeutic literature indicates that ferroptosis-targeted interventions in MDD-related models converge mainly on five interconnected modules: System Xc⁻/GSH/GPX4 restoration, Nrf2-dependent antioxidant defense, iron and lipid peroxidation control, inflammation–ferroptosis coupling, and mitochondrial or gut–brain metabolic regulation. This integrated view helps explain why multi-target interventions, especially natural products and traditional medicine-related therapies, are frequently represented in the current literature. At the same time, it also highlights a major limitation of the field: because many interventions regulate several pathways simultaneously, it remains difficult to determine whether ferroptosis suppression is the primary therapeutic mechanism or one component of a broader anti-stress, anti-inflammatory, and antioxidant response. Finally, studies using ferrostatin-1, deferoxamine, GPX4 knockdown/overexpression, or other causal rescue approaches carry higher evidentiary weight because they establish necessity or sufficiency of ferroptosis for the observed phenotype, and should be distinguished from studies reporting only marker-level changes.

5. Discussion

5.1. Mechanistic convergence and sublethal ferroptosis in MDD

The evidence summarized in this review indicates that ferroptosis provides a useful framework for integrating several pathological processes implicated in MDD. For many years, oxidative stress, neuroinflammation, mitochondrial dysfunction, glutamatergic disturbance, impaired neuroplasticity, and metabolic dysregulation have been discussed as important but partially disconnected mechanisms in depression. Ferroptosis offers a biological link among these processes because it is driven by iron-dependent lipid peroxidation and antioxidant system failure, while being highly sensitive to inflammatory and mitochondrial stress. In this sense, ferroptosis should not be regarded merely as another form of regulated cell death added to the list of depressive mechanisms. Rather, it may represent a convergent pathological process through which chronic stress, redox imbalance, and inflammatory activation are translated into persistent cellular dysfunction in mood-related brain regions.

A key feature of ferroptosis in MDD is that its relevance may extend beyond overt cell death. In classical experimental models of ferroptosis, the endpoint is often defined as iron-dependent membrane rupture and cell demise. However, depressive pathology is unlikely to be explained by massive neuronal loss alone. Many symptoms of MDD are more closely associated with impaired synaptic plasticity, altered neurotransmission, glial dysfunction, neuroinflammatory tone, and disrupted circuit adaptation. Therefore, in the context of depression, ferroptosis-related stress may exert pathogenic effects before irreversible cell death occurs. Sublethal lipid peroxidation, reduced GPX4 activity, impaired cystine uptake, iron dyshomeostasis, and mitochondrial oxidative injury may be sufficient to disturb neuronal excitability, astrocytic glutamate clearance, microglial inflammatory responses, and neurovascular homeostasis. This broader interpretation allows ferroptosis to be positioned not only as a death mechanism, but also as a mediator of cellular vulnerability and functional deterioration. The concept that non-lethal ferroptotic stress can impair neuronal function is supported by recent reviews of neuronal ferroptosis drivers [101].

5.2. Cell-type specificity and therapeutic implications

The available evidence also suggests that ferroptosis in MDD is unlikely to be confined to a single cell type. Neurons and neural progenitor cells are plausible primary targets because of their high metabolic demand, lipid-rich membranes, and dependence on mitochondrial function and antioxidant buffering. Ferroptosis-related injury in these cells may interfere with hippocampal neurogenesis, dendritic remodeling, and synaptic stability, all of which are closely related to stress resilience and antidepressant response. Microglia add another layer of complexity because they connect ferroptotic stress with inflammatory amplification. Inflammatory activation can enhance oxidative stress and lipid peroxidation, while ferroptosis-related lipid damage may further stimulate immune signaling. Astrocytes are particularly important because they regulate extracellular glutamate, provide metabolic and antioxidant support, and maintain neuron–glia communication. Emerging evidence on astrocytic ferroptosis and glutamate clearance highlights the possibility that glial ferroptotic vulnerability may indirectly reshape neuronal activity and depressive-like behavior. Although the strength of evidence differs across cell types, the overall pattern favors a multicellular interpretation rather than a neuron-centered model.

Another important insight from the current literature is that treatment-oriented research has progressed faster than cell-specific mechanistic clarification. A large number of studies have tested natural products, traditional medicine formulas, chemical agents, ferroptosis inhibitors, nutrients, microbial metabolites, and non-pharmacological interventions in MDD-related models. These interventions differ substantially in origin and pharmacological properties, yet they repeatedly converge on several molecular modules, including the System Xc⁻/GSH/GPX4 axis, Nrf2-centered antioxidant signaling, iron metabolism, lipid peroxidation, neuroinflammation, and mitochondrial or gut–brain metabolic regulation. This pattern is informative because it suggests that ferroptosis-targeted antidepressant strategies are rarely single-target interventions. Instead, most effective approaches appear to restore a broader protective network that restrains iron-driven oxidative injury and improves cellular resilience.

5.3. Clinical translation and broader pathological context

The prominence of natural products and traditional medicine-related interventions in this field is also worth noting. Many natural compounds and formulas have multi-component and multi-target properties, which may be particularly compatible with ferroptosis biology. Ferroptosis is not controlled by one isolated molecule, but by the balance among iron uptake and storage, phospholipid remodeling, antioxidant defense, inflammatory stress, and mitochondrial metabolism. Interventions that simultaneously modulate oxidative stress, inflammation, lipid peroxidation, and redox homeostasis may therefore be well suited to this network-like pathology. This does not mean that natural products are inherently superior to conventional pharmacological agents, nor does it mean that their antidepressant-like effects can be attributed solely to ferroptosis inhibition. Rather, the current evidence suggests that natural products and traditional interventions provide a rich pharmacological resource for exploring ferroptosis-related therapeutic mechanisms in MDD.

At the same time, ferroptosis should be positioned carefully within the broader pathophysiology of MDD. The current literature supports ferroptosis as an emerging mechanism and therapeutic target, but not as a standalone explanation for depression. MDD is a heterogeneous disorder involving genetic susceptibility, environmental stress, neuroendocrine dysregulation, immune activation, metabolic disturbance, and psychosocial factors. Ferroptosis may intersect with many of these processes, especially under conditions of chronic stress and inflammation, but its contribution is likely context-dependent. In some models, ferroptosis may act as a downstream consequence of oxidative and inflammatory injury; in others, it may amplify neuronal or glial dysfunction and promote behavioral abnormalities. This distinction is important because it determines whether ferroptosis should be targeted as a primary pathogenic driver, a disease amplifier, or a modifiable downstream vulnerability.

Overall, the findings reviewed here support a cautious but constructive view: ferroptosis is best understood as an integrative pathological and therapeutic framework in MDD rather than as a fully established central cause of the disorder. Its value lies in connecting molecular events such as iron dyshomeostasis, lipid peroxidation, and GPX4 dysfunction. Accordingly, ferroptosis-targeted strategies should currently be regarded as candidate, preclinical avenues rather than established antidepressant treatments, and their clinical antidepressant relevance remains to be established.

To bridge preclinical findings and clinical relevance, we propose a four-layer stratification framework for future studies: (i) QSM-based brain iron imaging to quantify regional iron deposition in MDD patients; (ii) peripheral blood markers including GPX4 activity, GSH/GSSG ratio, ACSL4, and PTGS2; (iii) lipid peroxidation indices such as plasma MDA, 4-HNE adducts, and oxidized phospholipid species; and (iv) inflammatory and metabolic profiles (e.g., IL-6, TNF-α, ferritin, transferrin saturation). Combining these layers in well-phenotyped MDD cohorts, ideally with longitudinal designs, could define ferroptosis-relevant endophenotypes and enable stratification for future targeted interventions.

6. Limitations and future perspectives

Despite increasing interest in ferroptosis in MDD, the current evidence remains largely preclinical. Most studies have relied on animal models or cell-based systems, including CUMS, CORT exposure, LPS challenge, post-stroke depression, sleep deprivation, TBI-associated depression, and other comorbidity-related models. These models provide useful mechanistic clues, but they capture different aspects of depressive pathology and cannot fully reproduce the clinical heterogeneity of MDD. Therefore, ferroptosis-related alterations observed in specific models should not be interpreted as universal mechanisms across all depressive disorders.

Finally, sex as a biological variable has not been explicitly addressed in the reviewed literature. Several key studies cited in this review (e.g., astrocytic PCBP1, reference 69) focus exclusively on male mice, while perimenopausal depression studies involving quercetin and Bushen Shugan Huayu are conducted in female or ovariectomized models. Given well-documented sex differences in MDD prevalence and in ferroptosis biology—including iron handling, GPX4/selenium status, and estrogen–Nrf2 interactions—future studies should systematically incorporate sex as a design variable and report sex-disaggregated ferroptosis outcomes.

Another important limitation is the way ferroptosis is commonly identified. Many studies infer ferroptosis from a limited set of markers, such as decreased GPX4 or SLC7A11, increased Fe²⁺, MDA, ACSL4, PTGS2, or altered ferritin-related proteins. Although these changes are compatible with ferroptosis, they overlap with oxidative stress, mitochondrial dysfunction, inflammation, and other forms of regulated cell death. Future studies should combine multiple lines of evidence, including iron dependency, lipid peroxide accumulation, GPX4 or System Xc⁻ dysfunction, rescue by ferroptosis inhibitors or iron chelators, and appropriate exclusion of other cell death pathways.

Cell-type specificity and causal validation also remain insufficient. Most available studies use bulk hippocampal, cortical, or hypothalamic tissue, making it difficult to determine whether ferroptosis occurs primarily in neurons, microglia, astrocytes, oligodendrocytes, endothelial cells, or other populations. Future work should incorporate cell-type-specific genetic manipulation, ferroptosis reporters, lipid peroxide imaging, single-cell sequencing, spatial transcriptomics, and brain-region-specific analysis. These approaches will be essential for determining whether ferroptosis is an initiating mechanism, an amplifier of stress-related injury, or a downstream consequence of inflammation and oxidative imbalance.

Therapeutic translation is still at an early stage. Many interventions, especially natural products and traditional medicine formulas, regulate multiple pathways simultaneously, including oxidative stress, inflammation, mitochondrial function, gut microbiota, and ferroptosis-related markers. This multi-target property may be beneficial, but it also makes it difficult to prove that ferroptosis inhibition is the primary mechanism underlying their antidepressant-like effects. Future studies should use ferroptosis-specific rescue or blockade strategies, establish clinically relevant biomarkers, and evaluate pharmacokinetics, brain delivery, dose–response relationships, and safety. Rather than treating ferroptosis as a universal explanation for MDD, future research should clarify when, where, and in which patient subgroups ferroptosis becomes a meaningful therapeutic target. To date, no human biomarker-guided or randomized clinical trial has directly tested whether a ferroptosis-targeted compound (e.g., iron chelator, GPX4 enhancer, or System Xc⁻ modulator) improves depressive symptoms in MDD patients, underscoring the substantial translational gap between preclinical mechanistic evidence and clinical application.

7. Conclusion

In this review, we have synthesized the current evidence linking ferroptosis to the molecular, cellular, and therapeutic landscape of major depressive disorder. The available data support ferroptosis as an integrative framework that connects iron dyshomeostasis, phospholipid peroxidation, and antioxidant defense failure to the cellular vulnerability and pathological networks implicated in MDD. However, the field remains at a preclinical association stage: most evidence derives from animal models and cell-based systems, causal validation is limited to a subset of studies, and no clinical stratification biomarker or randomized trial has yet established the antidepressant relevance of ferroptosis-targeted interventions. Accordingly, ferroptosis should currently be regarded as a promising but unproven therapeutic avenue in MDD rather than an established mechanism or treatment target. Future progress will depend on cell-type-specific causal validation, ferroptosis-selective biomarkers, and well-designed clinical studies that directly test ferroptosis-targeted strategies in carefully phenotyped patient subgroups.

CRediT authorship contribution statement

Deyue Kong: Writing – original draft. Ruiqi Duan: Investigation. Xiangyu Wang: Writing – review & editing. Xiaoyuan Wang: Writing – review & editing. Jie Zhao: Supervision.

Declaration of generative AI and AI-assisted technologies

During the preparation of this work, the authors used AI-assisted tools for literature organization, language editing, and revision tracking. After using these tools, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Funding

Shanxi Provincial Key Laboratory Project (No. 202504010931053), Shanxi Graduate Practice Innovation Project (No. 2025SJ394), Graduate Scientific Research Innovation Project of Shanxi University of Chinese Medicine (No. 2025SJ031).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by the Shanxi Provincial Key Laboratory Project (No. 202504010931053), the Shanxi Graduate Practice Innovation Project (No. 2025SJ394), and the Graduate Scientific Research Innovation Project of Shanxi University of Chinese Medicine (No. 2025SJ031).

Contributor Information

Deyue Kong, Email: kdy1252728345@163.com.

Ruiqi Duan, Email: 15135339052@163.com.

Xiangyu Wang, Email: 18434540553@163.com.

Xiaoyuan Wang, Email: wangxiaoyuanz@163.com.

Jie Zhao, Email: kdydls123@163.com.

Data availability

No data was used for the research described in the article.

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PERMALINK

Ferroptosis in major depressive disorder: Molecular mechanisms, cellular vulnerability, and therapeutic opportunities

Deyue Kong

Ruiqi Duan

Xiangyu Wang

Xiaoyuan Wang

Jie Zhao

Abstract

Highlights

1. Introduction

Table 1.

Table 2.

Table 3.

2. Molecular basis of ferroptosis relevant to depression

2.1. Iron dyshomeostasis and expansion of the labile iron pool

Fig. 1.

2.2. Lipid peroxidation and phospholipid remodeling

2.3. Failure of the System Xc−/GSH/GPX4 antioxidant axis

2.4. Human evidence: peripheral and central biomarkers in patients with MDD

3. Evidence linking ferroptosis to MDD: vulnerable brain regions, cellular involvement, and pathological networks

3.1. Ferroptosis-related alterations in depression models and vulnerable brain regions

3.2. Neuronal and neural progenitor ferroptosis: implications for neuroplasticity

3.3. Microglial ferroptosis and neuroinflammatory amplification

3.4. Astrocytic ferroptosis and glutamate homeostasis: emerging evidence

3.5. Other emerging cellular and systemic contributors

Fig. 2.

4. Therapeutic strategies targeting ferroptosis in MDD

4.1. Natural products and bioactive compounds

4.2. Traditional medicine formulas and traditional non-pharmacological interventions

4.3. Chemical agents, repurposed drugs, ferroptosis inhibitors, and biomedical interventions

4.4. Nutrients, microbial metabolites, and gut–brain axis-related interventions

4.5. Mechanistic convergence of ferroptosis-targeted interventions

5. Discussion

5.1. Mechanistic convergence and sublethal ferroptosis in MDD

5.2. Cell-type specificity and therapeutic implications

5.3. Clinical translation and broader pathological context

6. Limitations and future perspectives

7. Conclusion

CRediT authorship contribution statement

Declaration of generative AI and AI-assisted technologies

Funding

Declaration of competing interest

Acknowledgments

Contributor Information

Data availability

References

Associated Data

Data Availability Statement

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2.3. Failure of the System Xc⁻/GSH/GPX4 antioxidant axis