The metformin mediated MAPK signaling pathway influences D-Xylose regulation during diabetic kidney disease therapy

Diabetic kidney disease (DKD) is a major cause of end-stage renal disease. Although metformin is widely prescribed, the mechanisms underlying its renoprotective effects remain incompletely understood. We integrated multi-omics approaches—including network pharmacology, phosphoproteomics, and targeted metabolomics—in both db/db mice (male) and human patients. Analyses were performed on blood and kidney tissue from mice and paired blood/urine samples from DKD patients to identify conserved therapeutic targets and metabolic pathways. Metformin treatment improves glycemic control and renal function (reduced creatinine and urea nitrogen) in DKD mice. Network pharmacology and phosphoproteomic analyses reveal metformin’s engagement with the MAPK pathway, specifically through MAPK1 and MAPK3. Targeted metabolomics identifies four carbohydrate metabolites (mannitol, D-arabitol, D-mannose, and D-xylose) associated with DKD risk in humans. Cross-species validation in mice supports D-Xylose as a potential key biomarker for metformin’s therapeutic effects in DKD, with proximal tubule bicarbonate reclamation and alanine, aspartate and glutamate metabolism as key metabolic pathways. Metformin alleviates DKD through multi-modal mechanisms, modulating the MAPK signaling pathway and carbohydrate metabolites—notably D-xylose. As far as we are aware, these findings provide new mechanistic insights and suggest potential biomarker-driven strategies for DKD management. Diabetic kidney disease is a serious complication of diabetes in which the kidney becomes damaged. While metformin is a common medication used as a treatment, exactly how it impacts the kidneys is not fully clear. In this study, we analyzed samples from mice and humans with diabetic kidney disease. We found that metformin lowers blood sugar and alters the behavior of cells. These results help explain how metformin treatment can have a beneficial effect on kidney function and suggests new ways to monitor the effects of metformin on kidney function. Our findings may lead to more personalized strategies for managing diabetic kidney disease in the future. Xie, Zhu, Guo, Li et al. investigate the mechanism of action of metformin in diabetic kidney disease using multi-omics analyses in mouse models and human patients. The results show that metformin acts through the MAPK pathway and modulates carbohydrate metabolites, particularly D-xylose.