Abstract
Diabetic kidney disease (DKD), one of the most prevalent microvascular complications of diabetes mellitus, is characterized by a complex pathogenesis in which lipid metabolism dysregulation plays a central role. Increasing evidence indicates impaired lipophagy, a selective autophagic process responsible for degrading lipid droplets, contributes substantially to renal lipid accumulation and subsequent kidney injury in DKD. Natural medicines, leveraging their multi-target and multi-pathway regulatory properties, exert considerable therapeutic potential through modulation of lipophagy and restoration of lipid homeostasis. This review synthesizes current studies on the efficacy of natural medicines in enhancing renal lipophagy and attenuating lipid-mediated kidney injury in DKD. We systematically analyze major classes of natural medicines, including flavonoids, polyphenols, terpenoids, alkaloids, and polysaccharides, and discuss their mechanisms of action through key signaling pathways such as AMPK/mTOR, PPARα/γ, and SIRT1/FoxO1. These natural medicines effectively reduce renal lipid accumulation, mitigate oxidative stress and inflammation, and alleviate pathological damage in various DKD models. Their pleiotropic effects suggest promising therapeutic avenues for DKD through the restoration of lipophagic flux and lipid homeostasis. Nonetheless, significant challenges remain, including incomplete elucidation of precise molecular mechanisms and a scarcity of robust clinical validation. Future research must prioritize the rigorous identification of natural medicines, detailed mechanistic exploration, and well-designed clinical trials to translate the potential of natural medicine-mediated lipophagy regulation into effective therapeutic strategies for DKD.