Sotagliflozin provides additional benefits for high-fat diet-induced cardiac inflammatory injury by extra inhibiting P38MAPK and JNK

Abstract

SGLT1/2 dual-target inhibitors have demonstrated significant benefits for diabetic patients, particularly those with cardiovascular complications. However, pharmacological mechanisms beyond SGLT1/2 inhibition remain incompletely understood. The current study investigated the effects of sotagliflozin, a representative SGLT1/2 inhibitor, on obesity-related cardiomyopathy and explored the underlying molecular mechanisms. A high-fat diet-induced obese mouse model was employed to evaluate cardiac function and biochemical parameters, complemented by transcriptomic analysis and network pharmacology to identify potential therapeutic targets. Results demonstrated that sotagliflozin effectively ameliorated hyperglycemia, hyperlipidemia, and hypertension in obese mice while significantly improving obesity-induced cardiac dysfunction through suppression of myocardial inflammatory responses. Transcriptomic analysis revealed enrichment of differentially expressed genes in the MAPK pathway, which was further corroborated by network pharmacology. Both in vivo and in vitro validation confirmed direct binding of sotagliflozin to P38MAPK and JNK, leading to significant inhibition of their activation induced by palmitic acid or high-fat diet. These findings suggest that the cardioprotective effects of sotagliflozin against obesity-related cardiomyopathy are mediated through multi-target inhibition of P38MAPK and JNK pathways. Targeting inflammatory signaling pathways while managing cardiovascular risk factors may represent a promising therapeutic strategy for obesity-associated cardiovascular diseases.