Qianshi Mixture Treats Diabetic Nephropathy by Regulating Lipid Metabolism Reprogramming and Inhibiting Oxidative Stress Damage

ABSTRACT Diabetic nephropathy (DN) is a major complication of diabetes that can advance to end‐stage renal disease, posing a substantial health risk. The Qianshi Mixture (QSM) has shown therapeutic potential for DN; however, its pharmacological mechanisms remain insufficiently understood. We developed a DN model in mice and administered QSM as an intervention. To assess QSM's therapeutic effects, we measured the renal‐function‐related biochemical indicators and examined kidney pathological changes. We then applied transcriptomics and non‐targeted metabolomics to explore QSM's impact on gene expression and metabolic products within DN mice renal tissues. Based on our multi‐omics analysis, the effect of QSM on lipid‐metabolism‐related protein expression was confirmed by western blot in kidney tissue. Additionally, we evaluated the antioxidant and anti‐apoptotic properties of QSM by measuring oxidative stress indicators. QSM intervention improved hyperglycemia and proteinuria in DN mice. It also reduced key markers of renal dysfunction whilst alleviating pathological changes in kidney tissue. Through transcriptomic and metabolomic analyses, we identified that QSM affected genes and metabolites involved in lipid metabolism pathways. Notably, differentially expressed genes included Ces2h , Ces1f and Alox5 , whilst metabolites such as EPA, 9‐Oxo‐ODE and LPC (20:3) were altered. Further validation revealed that QSM increased the protein levels of CES2H and CES1F whilst decreasing the expression of FABP1, CD36, ALOX15 and ALOX5. Additionally, QSM reduced oxidative stress markers. QSM inhibited both oxidative stress and apoptosis in kidney tissues. QSM protects renal tissues in DN, likely through the regulation of lipid metabolism and the mitigation of oxidative stress damage.