Our results indicated that (i) exogenous H2S could attenuate mitochondrial fragments induced by hyperglycemia and hyperlipidemia in cardiomyocytes; (ii) exogenous H2S promoted the recruitment of parkin in mitochondria; and (iii) exogenous H2S promoted USP8 expression and the S-sulfhydration of USP8 facilitated the deubiquitination of parkin, enhancing mitophagy in cardiomyocytes. The gene discussed is PRKN; the disease is hyperlipidemia.