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  3. Molecular docking- and reporter-based screening identify dicoumarol against ER stress-induced liver injury in mice through inhibiting IRE1α activity

Molecular docking- and reporter-based screening identify dicoumarol against ER stress-induced liver injury in mice through inhibiting IRE1α activity

  • Life Sci. 2025 May 15:369:123526. doi: 10.1016/j.lfs.2025.123526.
Jifeng Yang 1,  Wei Luo 2,  Yanyu Chen 3,  Yimin Zhou 3,  Jiahai Wang 4,  Lin Mi 5,  Guojun Shi 6
Affiliations

Affiliations

  • 1 Joint Research Group of Metabolic Diseases and Biomaterials, Guangzhou University & The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 2 School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, China.
  • 3 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 4 Joint Research Group of Metabolic Diseases and Biomaterials, Guangzhou University & The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou 510006, China. Electronic address: jiahaiwang@gzhu.edu.cn.
  • 5 Joint Research Group of Metabolic Diseases and Biomaterials, Guangzhou University & The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou 510006, China. Electronic address: mlin@gzhu.edu.cn.
  • 6 Joint Research Group of Metabolic Diseases and Biomaterials, Guangzhou University & The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China. Electronic address: shigj6@mail.sysu.edu.cn.
PMID: 40049366 DOI: 10.1016/j.lfs.2025.123526
Abstract

Aims: Drug-induced liver injury is among the most challenging liver disorders. Endoplasmic reticulum (ER) is responsible for the correct protein folding and secretion, which are highly active in hepatocytes. Failure in maintaining the proper protein folding under pathological condition or external stimuli leads to the unfolded protein response (UPR) to restore ER homeostasis or induce cell death. IRE1α pathway is the most conserved UPR branch with diverse physiological and pathological functions. This study aimed to screen for natural compounds to alleviate hepatic ER stress and liver injury by modulating IRE1α activity.

Materials and methods: ATP-competitive molecules from chemical libraries were recognized by virtual screening for targeting the IRE1α kinase domain. IRE1α activity-based XBP1s-reporter cell lines with flow cytometric analysis were employed to validate candidates from chemical libraries. Then the functions of the top candidate compound on IRE1α signaling were analyzed followed by the treatment with ER stress agonists in vitro. Finally, the candidate compound was used to treat ER stress-induced acute liver injury to evaluate its protective effect in vivo.

Key findings: Dicoumarol (DIC) was discovered as a potential inhibitor of IRE1α activation in HEK293T cells, HepG2 cells and primary hepatocytes. Particularly, DIC ameliorates tunicamycin (Tm)- and carbon tetrachloride (CCl4)-induced acute hepatic ER stress to protect against liver injury.

Significance: This study established a drug screening strategy against IRE1α activation and identified potential new therapeutic effects of DIC in treating liver injury-related diseases.

Keywords

Dicoumarol; Drug screening; Endoplasmic reticulum stress; IRE1α; Liver injury; XBP1s-reporter.

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