FGF13 alleviates astrocytic apoptosis via JIP2 inhibition in the hippocampus and mitigates depression-like behavior

Major depressive disorder (MDD) is one of the leading causes of disability worldwide and significantly increases the risk of premature death and other diseases. Astrocyte loss is a key pathological hallmark of MDD, yet the underlying mechanisms remain unclear. Here, we identify fibroblast growth factor 13 (FGF13) as a critical regulator of astrocyte apoptosis in depression, which is closely associated with depression-like behaviors in mice. In depressive models, FGF13 expression is markedly reduced, particularly in astrocytes, accompanied by astrocyte apoptosis in the hippocampal region and decreased synaptic protein levels in the nervous system. Astrocyte-specific knockout of FGF13 induces astrocytic apoptosis, exacerbates inflammatory levels, and aggravates depression-like behaviors in mice. In contrast, astrocyte-specific overexpression of FGF13 significantly attenuates both astrocyte apoptosis and inflammation, and effectively ameliorates depression-like behaviors. Mechanistically, FGF13 directly binds to JIP2 protein, inhibits its activity, and subsequently blocks the downstream JIP2-JNK signaling pathway, thereby suppressing Bax/Bcl-2-mediated astrocyte apoptosis. These findings reveal a key mechanism by which FGF13 regulates astrocyte death in depression and highlight its potential as a therapeutic target for MDD, offering new insights for the development of antidepressant drugs targeting astrocytes.