Histone deacetylases inhibitor Chidamide mitigates inflammation and insulin resistance by targeting VDR in skeletal muscle cells.

The pathogenesis of Type 2 diabetes mellitus (T2DM) is heavily driven by exacerbated insulin resistance and inflammation in skeletal muscle, a major site for insulin-stimulated glucose uptake. Therefore, targeting inflammation and insulin resistance within this tissue represents an effective therapeutic strategy for T2DM. While histone deacetylase inhibitors (HDACi) exhibit therapeutic potential for metabolic diseases, the specific impact of the novel HDACi, Chidamide, on regulating skeletal muscle insulin resistance remains to be elucidated. Here, we provide in vitro evidence that Chidamide mitigates skeletal muscle inflammation and insulin resistance in a palmitic acid (PA)-induced C2C12 cell model. We demonstrate that Chidamide alleviates inflammation and activates the Akt/GSK3β/AS160-mediated insulin signaling thereby promoting cell-surface localization of GLUT4 and glucose uptake. Mechanistically, PA downregulates the expression of the vitamin D receptor (VDR), contributing to the inflammatory response and impairing Akt/GSK3β/AS160-mediated insulin signaling, which ultimately inhibited GLUT4-mediated glucose uptake. Chidamide effectively alleviates these effects by upregulating VDR transcription, potentially through the augmentation of histone H3 acetylation, thereby restoring insulin sensitivity and increasing GLUT4-mediated glucose uptake. In conclusion, our findings provide a proof-of-concept for the potential utility of Chidamide as a therapeutic strategy to enhance skeletal muscle insulin sensitivity.