Rewiring lipid metabolism in diabetic kidney disease: Pathogenic networks and the therapeutic convergence of natural products.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, and a growing body of evidence implicates disordered lipid metabolism as a central driver of its pathogenesis. This review examines renal lipid dysregulation in DKD along three interrelated axes: excessive lipid supply driven by CD36 and FATPs together with SREBP-mediated lipogenesis, impaired utilization arising from suppression of PPARα/PGC-1α/CPT1A-dependent fatty acid oxidation, and defective disposal due to ABCA1/ABCG1 downregulation. We describe how the lipotoxic accumulation of fatty acids, cholesterol, sphingolipids, and bile acids (BAs) activates a network of interconnected pathological circuits, encompassing mitochondrial dysfunction, ferroptosis, impaired lipophagy and mitophagy, and NLRP3-and TGF-β1-mediated inflammation and fibrosis. We further consider the emerging contribution of the gut-liver-kidney axis to the amplification of renal lipotoxicity. We then evaluate therapeutic strategies aimed at restoring lipid homeostasis, with particular emphasis on natural products - such as berberine, resveratrol, curcumin, and astragaloside IV - that exert multi-target renoprotection via PPARα, AMPK, SREBP1, Nrf2, and NLRP3 modulation. Finally, we highlight critical knowledge gaps and propose future directions for bridging mechanistic insight with clinical translation. Collectively, this framework offers an integrated roadmap for understanding lipotoxicity in DKD and for exploiting it therapeutically.