Vitamin D improves diabetic cardiomyopathy by inhibiting pyroptosis through the NOX4/NLRP3 inflammasome pathway

Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes mellitus, for which effective treatment options remain unavailable. Recent studies have demonstrated that vitamin D exerts protective effects against DCM, but its role in alleviating cellular pyroptosis remains uncertain. The present study aimed to investigate the ameliorative effects of vitamin D on pyroptosis in DCM and to elucidate the underlying molecular mechanisms. In the <i>in vivo</i> experiments, male diabetic db/db mice were treated with or without 1,25(OH)₂D₃ by oral gavage for 17 weeks, while age-matched non-diabetic db/m mice served as control group. In the <i>in vitro</i> experiments, H9c2 cardiomyocytes were exposed to normal glucose or high glucose and palmitic acid environment with or without 1,25(OH)₂D₃ treatment for 24 h. The results revealed that 1,25(OH)₂D₃ treatment significantly reduced body mass, food intake, water intake, and urine volume in db/db mice. Additionally, it improved fasting serum glucose levels, urine glucose levels, and glucose tolerance, while also enhancing insulin sensitivity and ameliorating dyslipidemia. Furthermore, 1,25(OH)₂D₃ alleviated myocardial hypertrophy, restored ultrastructural changes in cardiomyocytes, and improved cardiac systolic and diastolic functions. Both the <i>in vivo</i> and <i>in vitro</i> experiments showed that 1,25(OH)₂D₃ significantly downregulated the expression of proteins related to the NOX4/NLRP3 inflammasome pathway and pyroptosis. Specifically, in the <i>in vivo</i> models, 1,25(OH)₂D₃ effectively decreased the expression of genes linked to these pathways. In conclusion, this study provides evidence that vitamin D may improve DCM by inhibiting pyroptosis through the NOX4/NLRP3 inflammasome pathway. These findings highlight the therapeutic potential of vitamin D in managing DCM and underscore the importance of targeting pyroptosis.