HMGB1/STAT3/p65 axis drives microglial activation and autophagy exert a crucial role in chronic Stress-Induced major depressive disorder

•HMGB1/STAT3/p65 axis mediated microglial activation and autophagy in mPFC correlated with MDD were first identified, and HMGB1 was found to be a potential biomarker for MDD.•Increased HMGB1 expression was mainly observed in microglia from the medial prefrontal cortex of MDD model mice.•Specific knockdown of HMGB1 rescues chronic stress-induced depressive-related phenotypes, microglial activation, and autophagy in mice.•The effects induced by chronic stress were mimicked by exogenous administration of recombinant HMGB1 or specific overexpression of HMGB1, while blocked by STAT3 specific inhibitor or p65 knockdown.•Inhibition of HMGB1/STAT3/p65 axis prevented LPS-induced microglial activation and autophagy in vitro, which was reversed by recombinant HMGB1 protein overexpression.•Microglial HMGB1/STAT3/p65 axis within the mPFC is a novel therapeutic target in the treatment of MDD associated with stress.