FGF13 exerts neuroprotective effects via activation of the PI3K/AKT signaling pathway and serves as a potential...

Depression is a highly recurrent psychiatric disorder characterized by persistent low mood, anhedonia, and sleep disturbances. The clinical diagnosis of depression currently relies primarily on clinical interviews and standardized assessment scales, lacking objective biological markers. This increases the risk of misdiagnosis and missed diagnosis, while also limiting the precise differentiation of disease subtypes and the individualized prediction of treatment response. Identifying reliable biomarkers has therefore become a major research focus. This study, based on bioinformatics analysis of the GEO database, found that fibroblast growth factor 13 (FGF13) was significantly reduced in the serum of patients with major depressive disorder (MDD). FGF13 belongs to the fibroblast homologous factor (FHF) family and is enriched in neurons of the brain, where it regulates neuronal excitability and synaptic plasticity. However, the role of FGF13 in depression remains unclear. Based on the results of the bioinformatics analysis, experimental validation demonstrated that Fgf13 expression was significantly reduced in corticosterone (CORT)-induced PC12 and SH-SY5Y cells, as well as in the hippocampus of chronic unpredictable mild stress (CUMS) rats, as shown by qRT-PCR and Western blot analyses. Functional experiments demonstrated that FGF13 overexpression enhanced the expression of synaptic plasticity-related proteins (Syn, PSD95, BDNF) and anti-apoptotic protein (Bcl-2), while suppressing pro-apoptotic proteins (Bax, Cleaved-caspase-3) and activating the PI3K/AKT pathway. These effects were markedly reversed by treatment with the PI3K inhibitor LY294002. Furthermore, FGF13 overexpression improved neuronal apoptosis and morphological damage in the hippocampus of CUMS rats. Serum ELISA analysis revealed significantly reduced FGF13 levels in patients with depression. Logistic regression analysis showed a negative association between FGF13 expression and depression risk, while ROC analysis demonstrated good diagnostic performance (AUC = 0.936). Collectively, these findings suggest that FGF13 participates in the pathogenesis of depression by regulating synaptic plasticity and neuronal apoptosis and may serve as a promising biomarker and potential therapeutic target.