Molecular Crosstalk of Vitamin D3 with cGAS–STING and BDNF Pathways in a Rat Model of Chronic Stress

Neuroinflammation via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and reduced hippocampal brain-derived neurotrophic factor (BDNF) expression are key mechanisms underlying stress-induced depression. Vitamin D3, acting through the vitamin D receptor (VDR), is known to possess immunomodulatory and neurotrophic properties, but its role under chronic stress remains unclear. This study investigated the effects of vitamin D3 on chronic unpredictable mild stress (CUMS)-induced neuroinflammation and neurotrophic deficits in male Wistar rats. Thirty-two rats were divided into four groups: control, CUMS only, CUMS + vitamin D3 (1000 IU/kg), and CUMS + vitamin D3 (10,000 IU/kg). Vitamin D3 was injected intramuscularly three times weekly for 28 days. Hippocampal mRNA expression of cGAS-STING pathway markers, BDNF, microglial activation marker Iba1, and pro-inflammatory cytokines was quantified by RT-qPCR, and relative expression was calculated using the 2^-ΔΔCt method. Serum vitamin D3 and corticosterone concentrations were measured by ELISA. CUMS significantly reduced serum vitamin D3, increased corticosterone, activated hippocampal cGAS-STING signaling, upregulated inflammatory mediators and Iba1, and suppressed VDR and BDNF mRNA expression (all <i>p</i> < 0.05). Vitamin D3 administration effectively restored serum vitamin D3, normalized corticosterone levels, attenuated cGAS-STING activation and inflammatory gene expression, reduced microglial activation, and enhanced hippocampal VDR and BDNF mRNA expression (all <i>p</i> < 0.05). These findings demonstrate that vitamin D3 alleviates CUMS-induced hippocampal inflammation and neurotrophic deficits through coordinated modulation of immune signaling and BDNF, highlighting its potential as a therapeutic approach for stress-related brain disorders.