Asiatic acid inhibits endothelial-to-mesenchymal transition in diabetic kidney disease by reducing acetyl-CoA production via targeting ACSS2

Endothelial-to-mesenchymal transition (EndMT) is a critical contributor of renal fibrosis in diabetic kidney disease (DKD). Asiatic acid (AA), a natural triterpenoid compound, exhibits notable endothelial protective and anti-fibrotic properties; however, its impact on EndMT in DKD remains unclear. This study aimed to investigate the therapeutic effect of AA against EndMT in DKD and the underlying mechanisms. In vivo, AA effectively inhibited EndMT in the glomeruli of DKD mice, restored the expression of endothelial markers (CD31 and VE-cadherin), while reduced the expression of mesenchymal markers (α-SMA and Vimentin). Meanwhile, AA significantly reduced renal acetyl-CoA levels, which were elevated in DKD mice and strongly associated with EndMT progression. Mechanistically, acyl-CoA synthetase short-chain family member 2 (ACSS2) was identified as a key enzyme promoting acetyl-CoA production and histone acetylation, thereby facilitating EndMT. In vitro, exogenous acetate supplementation and siRNA mediated-ACSS2 knockdown confirmed ACSS2′s role in regulating EndMT. Pharmacological inhibition of ACSS2 further suppressed the progression of EndMT. Notably, molecular docking and cellular thermal shift assays revealed that AA directly binds to ACSS2. AA treatment reduced acetyl-CoA production, decreased H3K27 acetylation, restored endothelial characteristics, and suppressed mesenchymal features in both primary glomerular endothelial cells and endothelial cell lines. Overall, these findings demonstrate that AA inhibits EndMT in DKD by reducing acetyl-CoA production via targeting ACSS2. This study elucidates a novel mechanism by which AA attenuates renal fibrosis in DKD and highlights ACSS2 as a potential therapeutic target for intervention.