2. Academic Validation
  3. Discovery of a Novel Silybin Derivative for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis

Discovery of a Novel Silybin Derivative for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis

  • J Med Chem. 2025 Jun 26;68(12):12786-12799. doi: 10.1021/acs.jmedchem.5c00672.
Zhongtai Sui 1,  Mo Li 2 3,  Xueyi Wang 1,  Cailin Luo 1,  Ling Chen 1 2,  Xu Deng 1,  Mingjian Li 1,  Li Liu 1,  Xinyu Huang 1,  Xinyu Zhu 1,  Caiyun Nie 1,  Shuang Ni 1,  Junfeng Ye 1,  Shuhang Peng 4,  Bo Peng 4,  Zhengying Ma 4,  Zhiyong Luo 2,  Suyou Liu 1,  Dayou Ma 1
Affiliations

Affiliations

  • 1 Xiangya School of Pharmaceutical Sciences, Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha 410013, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Life Sciences, Xiangya School of Medicine, Central South University, Changsha 410013, China.
  • 3 School of Basic Medical Science, Xinjiang Medical University, Urumqi 830017, China.
  • 4 Changsha Jialimei Biotechnology Co., Ltd., Changsha 410013, China.
PMID: 40493802 DOI: 10.1021/acs.jmedchem.5c00672
Abstract

MASH has become the leading cause of liver disease worldwide, and the prevalence of MASH is steadily increasing. The development of new drugs for the treatment of MASH is urgent. Silybin has been used for decades in liver protection, but its insufficient antioxidant capacity and poor oral bioavailability have limited its clinical use. In this paper, we discovered a novel silybin derivative A2 as a potent agent for MASH treatment. In vitro, A2 showed excellent activity in inhibiting lipid accumulation, antioxidation, anti-inflammation, and antifibrosis. In the acute-liver-damage rat model experiment, A2 showed notable hepatoprotective efficacy. In the MASH mouse model experiment, A2, better than silybin, significantly ameliorated the pathological features of the MASH liver including steatosis, inflammation, and fibrosis. In addition, A2 displayed a good oral bioavailability and a good safety profile. Collectively, these findings demonstrated that A2 serves as a promising candidate for MASH treatment.

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