Targeting the FAPα/Integrin αvβ1 complex attenuates hepatic stellate cell activation and liver fibrosis

  • Biochem Pharmacol. 2026 May:247:117801. doi: 10.1016/j.bcp.2026.117801.
Chun Guan  1 ,  Nuo Cheng  1 ,  Yu Tong  1 ,  Yifei Li  1 ,  Jiayi Liu  1 ,  Haishan Luo  1 ,  Shihao Liu  1 ,  Jihai Chen  2 ,  Cong Wang  3
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, PR China.
  • 2. Department of Geriatric Endocrinology, Geriatric Hospital of Nanjing Medical University, Luojia Road 30, Nanjing 210024, PR China. Electronic address: [email protected].
  • 3. 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, PR China. Electronic address: [email protected].
PMID: 41687828 DOI: 10.1016/j.bcp.2026.117801
Abstract

Hepatic stellate cell (HSC) activation is central to liver fibrosis. Fibroblast activation protein α (FAPα) is highly expressed in activated HSCs, yet its regulatory role remains unclear. This study investigates the function and mechanism of FAPα in HSC activation and fibrosis progression. Using TGF-β1-induced LX2 cells and CCl4-induced mouse models, along with small-molecule inhibitors and multi-omics analyses, we found that inhibiting FAPα suppressed HSC activation, proliferation, migration, and ameliorated fibrosis. Notably, FAPα formed a functional complex with Integrin αvβ1 in activated HSCs. Dual inhibition of FAPα/Integrin αvβ1 more effectively attenuated HSC activation and fibrosis than single-agent treatment. Transcriptomic and proteomic studies revealed that the complex acts through the GPC3/FGF21 axis. This study identifies the FAPα/Integrin αvβ1 complex as a key regulator of liver fibrosis and provides a novel combinatory therapeutic strategy for anti-fibrotic drug development.

Keywords
Combination therapy; FAPα; Hepatic stellate cells; Integrinαvβ1; Liver fibrosis.
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