Targeting LRH-1 alleviates diabetes-induced lipotoxicity in podocytes: role of PLIN5-mediated lipid droplet turnover.

Diabetic kidney disease (DKD) is characterized by podocyte injury driven by intracellular lipid accumulation. Liver receptor homolog-1 (LRH-1) is a key nuclear receptor regulating lipid metabolism, yet its role in podocyte lipotoxicity remains unclear. This study identifies the LRH-1/perilipin 5 (PLIN5) axis as a critical pathway for maintaining lipid homeostasis in podocytes and a promising pharmacological target for DKD. We demonstrated that hyperglycemia suppressed the LRH-1/PLIN5 axis, leading to lipid droplet accumulation, oxidative stress, and podocyte injury in db/db mice and cultured podocytes. Activation of LRH-1 with agonist 1,2-dilauroyl-sn-glycerol-3-phosphocholine (DLPC) or its overexpression restored mitochondrial lipid utilization, reduced lysosomal lipotoxicity, and protected against renal injury by upregulating PLIN5. Furthermore, virtual screening of a natural product library identified chebulinic acid (CA) as a novel PLIN5-targeting agonist. CA treatment significantly upregulated PLIN5 expression, ameliorated lipid accumulation, and improved renal function in db/db mice. Our findings unveil the therapeutic potential of targeting the LRH-1/PLIN5 axis and present CA as a promising candidate for the treatment of diabetic podocytopathy.