<p>Depression is a prevalent mental disorder with poorly understood pathogenesis and often exhibits limited treatment response. Transient receptor potential vanilloid 1 (TRPV1) regulates glial activation and inflammatory responses, but its role in stress-related depressive pathophysiology remains elusive. Here, we investigated the effects of TRPV1 modulation on neuroinflammation and the impairment of neurogenesis underlying depression-like behaviors. Using a chronic social defeat stress (CSDS) mouse model, we evaluated the antidepressant potential of the TRPV1 antagonist capsazepine (CPZ) and agonist capsaicin (CAP) through behavioral assays. Then, hippocampal microglial activation, pro-inflammatory cytokine levels, neurogenesis, and the JAK2/STAT3 signaling pathway were assessed via Western blotting, ELISA, and immunofluorescence. The JAK2 agonist coumermycin A1 (CMA1) and viral-mediated TRPV1 knockdown were used to verify pathway involvement and target specificity. Our results showed that CPZ, but not CAP, effectively alleviated depression-like behaviors in CSDS mice. In CSDS-susceptible mice, TRPV1 and p-CaMKIIα levels were elevated, and CPZ treatment normalized their expression. CPZ also reduced microglial numbers and restored microglial morphology in the hippocampus, accompanied by decreased IL-6 and IL-1β production. Moreover, CPZ promoted neurogenesis in the dentate gyrus, as indicated by increased BrdU⁺ and DCX⁺ cells. Additionally, knockdown of TRPV1 enhanced stress resilience. Mechanistically, CPZ exerted these effects via inhibition of the JAK2/STAT3 signaling pathway, and CMA1-mediated activation of JAK2 reversed CPZ’s neuroprotective effects. Collectively, these findings reveal a microglia-mediated mechanism through which TRPV1 modulation ameliorates stress-induced neuroinflammation and impaired neurogenesis, identifying TRPV1 as a potential therapeutic target for depression.</p>