Astrocytic PCBP1 Suppresses Ferroptosis to Restore Glutamatergic Homeostasis and Mitigate Stress‐Induced Depression in Male Mice

Abstract Major depressive disorder (MDD) is a critical psychiatric illness with significant societal implications. The exact molecular mechanisms underlying MDD, specifically concerning cellular iron metabolism and ferroptosis, remain inadequately characterized. This study explores the regulatory function of astrocytic ferroptosis and its linkage to depressive‐like behaviors in mice under chronic unpredictable mild stress. Through integrated proteomic and phosphoproteomic analyses, it is identified that the iron‐chaperone protein polyC‐RNA‐binding protein 1 (PCBP1) is a critical regulator of ferroptosis in astrocytes within the ventral hippocampus (vHip), which is closely linked to depressive‐like behaviors in mice. The reduction in PCBP1 in astrocytes heightens their vulnerability to ferroptosis, resulting in depressive‐like behaviors under subthreshold stress conditions. Conversely, pharmacological inhibition of ferroptosis or overexpression of PCBP1 in astrocytes counteracts stress‐induced depressive‐like behaviors, indicating a protective function for PCBP1. Mechanistically, PCBP1‐mediated astrocytic ferroptosis compromises glutamate clearance and disrupts glutamatergic neuronal activity. Significantly, astrocyte‐specific overexpression of PCBP1 in vHip mitigates chronic stress‐induced glutamate toxicity and restores neuronal function, leading to improvements in depressive‐like behaviors. These results highlight the crucial role of PCBP1 in astrocytic ferroptosis and emphasize its potential as a therapeutic target for MDD, providing novel perspectives on the pathophysiology of stress‐induced depression.