<p>Depression is more prevalent among women, and while aerobic exercise serves as an effective nonpharmacological intervention, the potential mechanisms underlying its antidepressant effects remain incompletely understood. In basic research, chronic unpredictable mild stress (CUMS) is a widely used model of depression. In recent years, the cGAS-STING pathway has been demonstrated to be associated with depression as a component of innate immunity and a key driver of neuroinflammation. However, whether this pathway mediates the antidepressant effects of aerobic exercise remains to be elucidated. In this study, 36 female C57BL/6 mice were divided into a control group, a CUMS group, and a CUMS plus exercise group (CUMS + EX), with the CUMS + EX group undergoing a six-week treadmill training program. A multimodal approach was used, integrating behavioural assessment, hippocampal histopathological analysis, and molecular analysis of neuroinflammatory pathways, neurotransmitters, and sex hormones. The findings revealed that exercise intervention significantly ameliorated CUMS-induced depressive-like behaviour in female mice. This improvement was accompanied by reduced hippocampal neuronal damage, suppressed glial cell activation, and decreased levels of proinflammatory cytokines (IL-6, IL-1β, TNF-α). Furthermore, it restored the homeostasis of monoamine neurotransmitters (5-HT, DA, and NE) and regulated the imbalance of serum sex hormones. Mechanistically, exercise significantly suppressed the activation of the cGAS-STING signalling pathway and downregulated key proteins in the NF-κB pathway. In summary, our findings indicate that aerobic exercise alleviates depressive-like behaviour in female mice by inhibiting a cascade of responses triggered by neuroinflammation mediated through the hippocampal cGAS/STING/NF-κB pathway. These findings provide novel mechanistic insights into the antidepressant effects of exercise and suggest that the cGAS-STING pathway may serve as a therapeutic target.</p>