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

  • Ren Fail. 2026 Dec;48(1):2670806. doi: 10.1080/0886022X.2026.2670806.
Qian Guan  1  2  3  4 ,  Zijing Zhu  1  2 ,  Hongtu Hu  1  2 ,  Juan Wang  1  2 ,  Yanqin Fan  1  2 ,  Peng Ye  5 ,  Qian Yang  1  2 ,  Guohua Ding  1  2 ,  Jijia Hu  1  2
Affiliations
  • 1. Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 2. Nephrology and Urology Research Institute of Wuhan University, Wuhan University, Wuhan, China.
  • 3. Department of Nephrology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4. Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5. Division of Urology, Shenzhen Hospital of Southern Medical University, Shenzhen, China.
PMID: 42135621 DOI: 10.1080/0886022X.2026.2670806
Abstract

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.

Keywords
Chebulinic acid (CA); LRH-1; PLIN5; diabetic podocytopathy; lipotoxicity.
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