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

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Original 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.

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