Xiaoyu Xiezhuo Decoction Improves Diabetic Kidney Disease by Regulating Cysteine and Methionine Metabolism

Background: Diabetic kidney disease (DKD) is a major complication of diabetes mellitus and has emerged as a significant global public health concern. In this study, we aimed to evaluate the therapeutic effects of the traditional Chinese medicine compound formula, Xiaoyu Xiezhuo decoction (XXD), in a DKD mouse model and to explore its underlying molecular mechanisms using integrated transcriptomic and metabolomic approaches. Methods: We established a DKD mouse model by feeding mice a high‐sugar, high‐fat diet and administering streptozotocin. We then treated the mice with XXD. To assess the therapeutic effects of XXD, we measured renal function and performed histopathological staining of kidney tissues. We used transcriptomics and metabolomics analyses to investigate how XXD modulated gene expression and metabolite profiles in the renal tissue of DKD mice. Based on the integrated transcriptomic and nontargeted metabolomic data, we further validated the effects of XXD on key factors involved in the cysteine and methionine metabolism pathway, as well as on markers of inflammation and oxidative stress. Results: XXD effectively reduced blood glucose levels, decreased proteinuria, alleviated renal pathological injury, and slowed disease progression in DKD mice. Transcriptomic and metabolomic analyses revealed that XXD significantly upregulated the expression of Gnmt , Ahcy , and Cth and attenuated oxidative stress and inflammation in renal tissue. These effects were associated with the regulation of key metabolites—including methionine sulfoxide, methionine, S‐adenosylmethionine, L‐cysteine, and L‐serine—in the cysteine and methionine metabolism pathway. Western blot analysis confirmed that XXD treatment increased the protein expression of GNMT, AHCY, and CTH in kidney tissues. Furthermore, XXD markedly reduced the expression of proinflammatory factors and enhanced antioxidant enzyme activity, thereby mitigating oxidative stress in DKD kidneys. Conclusion: XXD alleviates renal injury in DKD mice by exerting anti‐inflammatory and antioxidant effects through the modulation of the cysteine and methionine metabolism pathway.