BACKGROUND: Diabetic nephropathy (DN) is often accompanied by dysregulated lipid metabolism, which exacerbates renal injury. Keluoxin (KLX), a therapeutic agent approved by the National Medical Products Administration of China, has demonstrated efficacy in treating DN. However, the mechanisms underlying KLX's beneficial effects, particularly its role in lipid metabolism regulation, remain poorly understood. PURPOSE: To investigate the molecular mechanisms by which KLX ameliorates ectopic lipid deposition (ELD) in DN. METHODS: Spontaneous diabetic nephropathy was induced in KKAy mice, which were then administered oral KLX at doses of 0.9 g/kg or 1.8 g/kg for 12 weeks. The effects of KLX on blood glucose, lipid profiles, proteinuria, and renal function were evaluated. Pathological changes, with a particular focus on ELD, were assessed using Masson's trichrome staining, PASM staining, electron microscopy, and Oil Red O staining. The regulation of the AMPK/NFκB signaling axis was examined through RT-qPCR and Western blotting. In vitro, high-glucose/high-fat conditions were employed to simulate a diabetic environment. The effects of KLX on mesangial cell proliferation and fibrosis under glucolipotoxic conditions were assessed using ROS staining, EDU staining, and SMA staining. To confirm the role of AMPK in KLX-mediated renal protection, the AMPK inhibitor compound C were used for further validation. RESULTS: KLX treatment significantly reduced blood glucose levels (p<0.01), urinary protein excretion (p<0.05; p<0.01), and serum creatinine and blood urea nitrogen levels (p<0.01), improving renal function in DN mice. Histological analysis revealed that KLX alleviated mesangial expansion, matrix thickening, and renal fibrosis, thus preserving renal structure. It also led to a reduction in peripheral blood triglyceride levels (p<0.01) and mitigated lipid accumulation in both the liver and kidneys. KLX downregulated the mRNA expression of genes associated with lipid synthesis (Fasn, Srebp1, Acc) and fibrosis (Fn1, Pai1), while upregulating the expression of genes involved in lipid breakdown (Cpt1, Cpt2) and antioxidant defense (Sod2, Sod3, Cat). This treatment also enhanced the expression of AMPK and phosphorylated(p) AMPK, while inhibiting NFκB and pNF-κBp65. In vitro, compound C partially inhibited the effects of KLX, and subsequent experiments confirmed that KLX exerts its lipid-regulatory effects through the AMPK/NF-κB axis, thereby attenuating mesangial cell proliferation, fibrosis, and oxidative stress. CONCLUSION: These findings provide compelling evidence that KLX regulates lipid metabolism via the AMPK/NFκB axis, inhibiting lipid synthesis and promoting fatty acid oxidation. By reducing ELD, KLX protects renal structure and function in DN, offering a promising therapeutic approach for this condition.