Hydrogen sulfide (H₂S), as a gasotransmitter, is involved in various pathophysiological processes. Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus (DM), which leads to structural and functional abnormalities of the myocardium and eventually causes heart failure (HF). Systolic and diastolic dysfunction are fundamental features of heart failure. SERCA2a, as a key enzyme for calcium transport in the endoplasmic reticulum (ER), affects the process of myocardial relaxation and contraction. H₂S can protect the cardiac function against diabetic hearts, however, its mechanisms are unclear. This study found that exogenous H₂S affects cellular calcium transport by regulating the H₂S/MuRF1/SERCA2a/cardiac contractile pathway. Our results showed that, compared with the db/db mice, exogenous H₂S restored the protein expression levels of CSE and SERCA2a, and the activity of SERCA2a, while reducing cytosolic calcium concentrations and MuRF1 expression. We demonstrated that MuRF1 could interact with SERCA2a via co-immunoprecipitation. Using LC-MS/MS protein ubiquitylation analysis, we identified 147 proteins with increased ubiquitination levels, including SERCA2a, in the cardiac tissues of the db/db mice compared with NaHS-treated db/db mice. Our studies further revealed that NaHS administration modified MuRF1 S-sulfhydration and enhanced the activity and expression of SERCA2a. Under hyperglycemia and hyperlipidemia, overexpression of the MuRF1-Cys44 mutant plasmid reduced the S-sulfhydration level of MuRF1 and decreased the ubiquitination level of SERCA2a and the intracellular Ca²⁺ concentration. These findings suggested that H₂S modulates SERCA2a ubiquitination through MuRF1 S-sulfhydration of Cys44 to prevent decreased myocardial contractility due to increased cytosolic calcium.

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