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 experiments, male diabetic db/db mice were treated with or without 1,25(OH)D by oral gavage for 17 weeks, while age-matched non-diabetic db/m mice served as control group. In the experiments, H9c2 cardiomyocytes were exposed to normal glucose or high glucose and palmitic acid environment with or without 1,25(OH)D treatment for 24 h. The results revealed that 1,25(OH)D 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)D alleviated myocardial hypertrophy, restored ultrastructural changes in cardiomyocytes, and improved cardiac systolic and diastolic functions. Both the and experiments showed that 1,25(OH)D significantly downregulated the expression of proteins related to the NOX4/NLRP3 inflammasome pathway and pyroptosis. Specifically, in the models, 1,25(OH)D 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.