2. Academic Validation
  3. Vitamin D receptor agonists inhibit liver fibrosis by disrupting the interaction between hepatic stellate cells and neutrophil extracellular traps

Vitamin D receptor agonists inhibit liver fibrosis by disrupting the interaction between hepatic stellate cells and neutrophil extracellular traps

  • Biochem Pharmacol. 2025 Jun 24:240:117059. doi: 10.1016/j.bcp.2025.117059.
Xuwentai Liu 1,  Yue Wu 2,  Chun Guan 2,  Nuo Cheng 2,  Xueting Wang 3,  Yichen Liu 2,  Jihai Chen 4,  Cong Wang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, China; Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Institute of Special Environmental Medicine, Nantong University. No.9, Seyuan Road, Chongchuan District, Nantong, Jiangsu 226009, China.
  • 4 Department of Geriatric Endocrinology, Geriatric Hospital of Nanjing Medical University, Luojia Road 30, Nanjing 210024, China. Electronic address: nanjingchenjh@126.com.
  • 5 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, China. Electronic address: wangcong@cpu.edu.cn.
PMID: 40571206 DOI: 10.1016/j.bcp.2025.117059
Abstract

Liver fibrosis is a progressive condition driven by the activation of hepatic stellate cells (HSCs), with neutrophil extracellular traps (NETs) playing a crucial role in exacerbating this process. Recent research has highlighted the vitamin D receptor (VDR) as a critical regulator in fibrosis, offering a potential therapeutic target. This study investigates the molecular mechanisms by which the novel non-steroidal VDR agonist 16i inhibits liver fibrosis. Using both in vitro and in vivo models, we found that 16i effectively disrupts the positive feedback loop between NET formation and HSC activation by downregulating fibroblast activation protein alpha (FAPα), a key protein in fibrogenesis. Mechanistically, 16i activates VDR, leading to the formation of a VDR-Retinoid X Receptor (RXR) complex that competitively inhibits the binding of transcriptional activators to the FAPα promoter. This downregulation results in reduced HSC activation and decreased secretion of pro-inflammatory cytokines, thereby attenuating fibrogenic signaling pathways. These findings suggest that 16i offers a promising molecular approach for the treatment of liver fibrosis by targeting the underlying mechanisms of HSC activation and NET formation.

Keywords

Hepatic stellate cells; Liver fibrosis; Neutrophil extracellular traps; Vitamin D receptor.

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