<p>Mitochondrial dysfunction, driven by genetic susceptibility or environmental insults, contributes to the pathogenesis of neurodegenerative disorders, including Parkinson’s disease (PD). Mitophagy is a selective pathway that eliminates dysfunctional mitochondria, and mitophagy inducers hold therapeutic promise for neurodegeneration. However, the arsenal of specific, clinically viable inducers remains limited. ADT-OH, a slow-release H₂S compound, was recently reported to induce mitochondrial uncoupling through sulfide-quinone oxidoreductase (SQR)-mediated oxidation of H₂S. In this study, we report that ADT-OH elicits mitophagic flux in microglia. This is evidenced by the reduced steady-state levels of mitochondrial marker proteins (TOM20, COXIV, and HSP60), enhanced mitochondrial fission dynamics, and mitochondrial translocation into lysosomes, as visualized by the mt-Keima probe. Mechanistically, its mitophagy-promoting effect is dependent on SQR-mediated mitochondrial uncoupling and subsequent activation of PINK1-PARKIN signaling. Importantly, ADT-OH abrogates the accumulation of dysfunctional mitochondria and the subsequent cytosolic release of mitochondrial DNA in α-synuclein preformed fibrils (α-Syn PFF)-challenged microglia, thereby blunting the activation of the cGAS-STING pathway and the downstream production of inflammatory mediators. Furthermore, systemic administration of ADT-OH dampened microglial activation and cGAS expression in α-Syn-overexpressing PD mice, thereby mitigating the loss of midbrain dopaminergic neurons and ameliorating motor coordination deficits. Collectively, our findings demonstrate that ADT-OH exerts robust neuroprotective effects in PD models, both in vitro and in vivo, by enhancing mitophagy and inhibiting microglia-mediated neuroinflammation.</p>