2. Academic Validation
  3. Targeting cholangiocyte sphingosine-1-phosphate (S1P) receptor 1 signaling alleviates cholestatic liver injury: Mechanistic insight into S1P/phosphorylated signal transducer and activator of transcription 3 axis

Targeting cholangiocyte sphingosine-1-phosphate (S1P) receptor 1 signaling alleviates cholestatic liver injury: Mechanistic insight into S1P/phosphorylated signal transducer and activator of transcription 3 axis

  • J Pharmacol Exp Ther. 2026 Apr;393(4):104306. doi: 10.1016/j.jpet.2026.104306.
Zihang Yuan 1,  Jie Wang 1,  Haoran Zhang 1,  Yingying Miao 1,  Yuanyuan Chai 1,  Anqin Li 1,  Qianhui Tang 1,  Qingyu Chen 1,  Luyong Zhang 2,  Qinwei Yu 3,  Zhenzhou Jiang 4
Affiliations

Affiliations

  • 1 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
  • 2 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China.
  • 3 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China. Electronic address: [email protected].
  • 4 New Drug Screening and Pharmacodynamics Evaluation Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, China. Electronic address: [email protected].
PMID: 41818851 DOI: 10.1016/j.jpet.2026.104306
Abstract

Effective first-line treatments for cholestasis are limited, leading to poor outcomes and liver transplantation after ursodeoxycholic acid/obeticholic acid intolerance. We investigated the role of cholangiocyte sphingosine-1-phosphate receptor 1 (S1PR1) in cholestasis pathogenesis to identify new therapeutic targets. We generated cholangiocyte-specific S1PR1 knockout mice (S1PR1Δintrahepatic biliary epithelial cell). Cholestasis models included bile duct ligation (BDL) (14 days) and 0.5% cholic acid (CA) diet (4 months). The level of sphingosine-1-phosphate (S1P) and its receptor, especially S1PR1 in cholangiocytes were significantly increased in both BDL or 0.5% CA diet models. Sphingosine kinase 1-derived sphingosine-1-phosphate from hepatic stellate cells/endothelial cells activated cholangiocyte S1PR1, promoting signal transducer and activator of transcription 3 phosphorylation and releasing interleukin-6/C-C motif chemokine 7, which remodeled the inflammatory microenvironment and exacerbated liver injury. S1PR1 deletion significantly reduced liver injury, fibrosis, and inflammation. Likewise, treatment with a specific inhibitor of cholangiocyte S1PR1, W146, slightly improved liver injury induced by BDL. The functional effect of S1PR1 in cholangiocyte was further strengthened by our design of the nanoparticle-delivered W146. This demonstrated that cholangiocytes-specific deletion of S1PR1 can alleviate liver fibrosis and injury caused by biliary obstruction or chronic cholestasis, which helps to develop S1PR1 as a target for the treatment of liver fibrosis and cholestasis. SIGNIFICANCE STATEMENT: This study identifies elevated sphingosine-1-phosphate as a potential cholestasis biomarker. High sphingosine-1-phosphate binds sphingosine-1-phosphate receptor 1, activating signal transducer and activator of transcription 3 in cholangiocytes and creating proinflammatory microenvironment. Cholangiocyte-specific sphingosine-1-phosphate receptor 1 inhibition via nanocrystal agents alleviates cholestatic liver injury.

Keywords

Cholangiocytes; Cholestasis; Sphingosine-1-phosphate; phingosine-1-phosphate receptor 1.

Figures
Products