The Ferroptosis–Mitochondrial Axis in Depression: Unraveling the Feedforward Loop of Oxidative Stress, Metabolic Homeostasis Dysregulation, and Neuroinflammation

作者：Xu Liu, Qiang Luo, Yulong Zhao, Peng Ren, Jin Yu, Junjie Zhou · 发表于：Antioxidants · 年份：2025 · DOI：10.3390/antiox14050613 · 被引用次数：49 · 研究领域：Ferroptosis and cancer prognosis、interferon and immune responses、Immune cells in cancer

Emerging evidence links ferroptosis-mitochondrial dysregulation to depression pathogenesis through an oxidative stress-energy deficit-neuroinflammation cycle driven by iron overload. This study demonstrates that iron accumulation initiates ferroptosis via Fenton reaction-mediated lipid peroxidation, compromising neuronal membrane integrity and disabling the GPx4 antioxidant system. Concurrent mitochondrial complex I/IV dysfunction impairs ATP synthesis, creating an AMPK/mTOR signaling imbalance and calcium dyshomeostasis that synergistically impair synaptic plasticity. Bidirectional crosstalk emerges: lipid peroxidation derivatives oxidize mitochondrial cardiolipin, while mitochondrial ROS overproduction activates ACSL4 to amplify ferroptotic susceptibility, forming a self-reinforcing neurodegenerative loop. Prefrontal-hippocampal metabolomics reveal paradoxical metabolic reprogramming with glycolytic compensation suppressing mitochondrial biogenesis (via PGC-1α/TFAM downregulation), trapping neurons in bioenergetic crisis. Clinical data further show that microglial M1 polarization through cGAS-STING activation sustains neuroinflammation via IL-6/TNF-α release. We propose a "ferroptosis-mitochondrial fragmentation-metabolic maladaptation" triad as mechanistic subtyping criteria for depression. Preclinical validation shows that combinatorial therapy (iron chelators + SIRT3 agonists) rescues neuronal viability by restoring mitochondrial integrity and energy flux. This work shif...