BACKGROUND Diabetic nephropathy (DN) is a major complication of diabetes, marked by progressive renal damage and an inflammatory response. Although research has investigated the pathological mechanisms underlying DN, effective treatment options remain limited. AIM To evaluate the therapeutic impact of Shenzhuo formulation (SZF) on a DN mouse model and to examine its potential molecular mechanisms using transcriptomic and metabolomic approaches. METHODS We established a DN mouse model through a high-fat diet combined with streptozotocin (STZ) injection, followed by SZF treatment. We analyzed SZF's effects on gene expression and metabolite profiles in renal tissues of DN mice using transcriptomics and metabolomics techniques. Additionally, based on transcriptomic and non-targeted metabolomic findings, we further assessed SZF's influence on the expression of factors related to the cytochrome P450 (CYP450)-mediated arachidonic acid (AA) metabolism pathway, as well as its effects on inflammation and oxidative stress. RESULTS SZF intervention significantly decreased hyperglycemia and mitigated renal function impairment in DN mice. Pathological analysis revealed that SZF treatment improved renal tissue damage, reduced fibrosis, and diminished glycogen deposition. Transcriptomic analysis indicated that SZF influenced mRNA expression of CYP450-related genes, including Cyp2j13, Cyp2b9, Pla2 g2e/Cyp4a12a, Cyp4a32, Cyp2e1, and Cyp4a14. Non-targeted metabolomic results demonstrated that SZF altered the levels of metabolites associated with the AA metabolic pathway, including 5,6-EET, 14,15-EET, phosphatidylcholine, and 20-HETE. Further experiments showed that SZF upregulated the expression of CYP4A and CYP2E proteins in renal tissue, as well as CYP2J and CYP2B proteins. Additionally, SZF significantly reduced the expression of inflammatory factors in renal tissue, enhanced antioxidant enzyme activity, and alleviated oxidative stress. CONCLUSION SZF exerts anti-inflammatory and antioxidant effects by regulating CYP450-mediated AA metabolism, leading to improved renal function and improved pathological state in DN mice.