Jujuboside A ameliorates glomerular podocytes lipotoxicity in diabetic mice by YY1-mediated promotion of intracellular cholesterol transport and efflux.

Glomerular podocytes injury represents a critical pathological hallmark of diabetic kidney disease (DKD), in which lipotoxicity plays a central pathogenic role. Our previous investigations in type 2 diabetes mellitus (T2DM) have demonstrated that Jujuboside A (Ju A), a triterpene saponin isolated from Semen Ziziphi Spinosae (SZS), exerted dual therapeutic effects in T2DM by ameliorating hepatic steatosis and renal dysfunction. However, the role of podocytes lipid metabolism in Ju A-mediated protection against DKD remain undefined prior to the present study. In this work, we reported that Ju A significantly attenuated glomerular podocytes injury and lipotoxicity in DKD, while concurrently improving renal function and preserving glomerular morphology. Mechanistically, Yin Yang 1 (YY1)-mediated alleviation of lipotoxicity contributed to the protective effect of Ju A against glomerular podocytes injury, primarily by promoting intracellular cholesterol transport and efflux. In conclusion, our findings demonstrated that Ju A mitigated lipid overload in glomerular podocytes by modulating cholesterol homeostasis via YY1, which not only intercepted the pathological progression of DKD but also provided a potential therapeutic target (YY1) and candidate agent (Ju A) for DKD intervention.