The m6A Reader IGF2BP2 Drives Depressive-like Behaviors Through m6A-Dependent Repression of Astrocytic GLUT1 and Glucose Metabolism

Major depressive disorder (MDD) is a severe psychiatric condition with complex etiology and limited therapeutic targets. In this study, we identify the m6A reader protein IGF2BP2 as a critical epigenetic regulator in depression. We demonstrate that IGF2BP2 expression is significantly upregulated in the hippocampus of both MDD patients and mice subjected to chronic unpredictable mild stress (CUMS). Further, hippocampal knockdown of Igf2bp2 ameliorated depressive-like behaviors in mice. Mechanistically, we demonstrated that the IGF2BP2 protein, specifically in astrocytes, binds to the mRNA of glucose transporter 1 (GLUT1) and regulates the expression of GLUT1 in an m6A-dependent manner, mainly by promoting its decay, leading to impaired astrocytic glucose uptake. Moreover, overexpression of Glut1 rescued both glucose metabolic deficits and depressive-like behaviors. Taken together, our findings reveal a previously unrecognized IGF2BP2-GLUT1 axis in the pathogenesis of depression and highlight its potential as a therapeutic target for antidepressant intervention.