2. Academic Validation
  3. Discovery of novel FABP1 inhibitors for the treatment of metabolic dysfunction-associated steatohepatitis and hepatic fibrosis

Discovery of novel FABP1 inhibitors for the treatment of metabolic dysfunction-associated steatohepatitis and hepatic fibrosis

  • BMC Chem. 2025 Sep 30;19(1):270. doi: 10.1186/s13065-025-01630-y.
Zongtao Zhou # 1 2,  Zhonghui Luo # 3,  Xudong Lv # 4,  Lianru Chen 2,  Zhihong Qin 2,  Qi Ma 2,  Zheng Li 5,  Deyang Kong 6
Affiliations

Affiliations

  • 1 Shenzhen Bao'an District Songgang People's Hospital, Shenzhen, 518105, People's Republic of China.
  • 2 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China.
  • 3 The First Affiliated Hospital, Department of Anaesthesiology, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China.
  • 4 Department of Ophthalmology, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437100, People's Republic of China.
  • 5 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People's Republic of China. li.zheng.sky@163.com.
  • 6 Shenzhen Bao'an District Songgang People's Hospital, Shenzhen, 518105, People's Republic of China. kdy8777@163.com.
  • # Contributed equally.
PMID: 41029781 DOI: 10.1186/s13065-025-01630-y
Abstract

The fatty acid-binding protein 1 (FABP1) has drawn increasing attention as a promising target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). However, efforts to validate pharmacological effects of FABP1 are restricted by the lack of relevant inhibitors. Herein, we identified the lead compound 1 with potent inhibition on FABP1 through screening from our in-house library. Further comprehensive structure-activity relationship (SAR) study based on compound 1 resulted in the identification of the optimal compound 12 (IC50 = 3.6 µM). Moreover, compound 12 exerted stronger efficacy on reducing hepatic lipid accumulation, inflammation and fibrosis than that of clinical candidate GFT505 in MASH models. In addition, compound 12 significantly inhibited fibrosis-related gene expression in TGF-β treated hepatic stellate cells and exerted stronger effects than Pirfenidone in CCl4-induced liver fibrosis mice model. These results indicated that compound 12 may serve as a novel FABP1 inhibitor for the treatment of MASH and liver fibrosis.

Keywords

Compound 12; FABP1; Inflammation; Liver fibrosis; MASH.

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