Abstract

Hydrogen sulfide (H2S) is well-known for its role as a gasotransmitter with cardioprotective properties, particularly in the context of diabetic cardiomyopathy (DCM). However, its molecular mechanisms are not completely defined. The current study outlines how H2S alleviates DCM through combination of network pharmacology and experimental validations. A spontaneous type 2 diabetes-associated DCM model was developed using db/db mice which were treated with the H₂S donor sodium hydrosulfide (NaHS) for 8 weeks. The functional, histological, and molecular evaluations were broadly analyzed for the cardiac protective effects of H2S. NaHS treatment significantly attenuated myocardial fibrosis and inflammation in db/db mice, which thereby leading to a pronounced improvement in cardiac function. Network pharmacology analyses identified 121 overlapping targets between H₂S and DCM, which were enriched in various signaling pathways mainly associated with inflammation and ECM remodeling. Topological analysis indicated that the JAK2/STAT3 signaling pathway serves as a crucial mediator, with STAT3 identified as a central hub among various analytical modules. According to the experimental results, the JAK2/STAT3 signaling was significantly activated in both diabetic hearts and high-glucose stimulated cardiac fibroblasts. In contrast, H₂S treatment significantly inhibited this activation. More importantly, the pharmacological reactivation of STAT3 largely reversed the protective effects of H₂S both in vivo and in vitro. Taken together, our results demonstrate that H₂S alleviates DCM via inhibiting inflammatory and fibrotic responses that associated with JAK2/STAT3 signaling pathway. This study provides a mechanistic insight into H₂S-mediated cardioprotection and it highlights the JAK2/STAT3 signaling as a potential therapeutic target in DCM.