2. Academic Validation
  3. High-throughput screening identifies a dual-activity inhibitor of OXCT1 for hepatocellular carcinoma therapy

High-throughput screening identifies a dual-activity inhibitor of OXCT1 for hepatocellular carcinoma therapy

  • Bioorg Chem. 2025 Sep 5:165:108964. doi: 10.1016/j.bioorg.2025.108964.
Rui Liu 1,  Yuchen Sun 1,  Shengqi Shen 2,  Tingting Li 3,  Nanchi Xiong 1,  Wenhao Ma 1,  Zilong Zhou 1,  Haiying Liu 1,  Yiyang Chu 1,  Mingming Wang 1,  Xue Ai 1,  Ling Ye 4,  Huafeng Zhang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China; Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
  • 2 Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China.
  • 3 State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China.
  • 4 State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China; Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China. Electronic address: yeling10@ustc.edu.cn.
  • 5 State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China; Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China. Electronic address: hzhang22@ustc.edu.cn.
PMID: 40925224 DOI: 10.1016/j.bioorg.2025.108964
Abstract

3-Oxoacid CoA-transferase 1 (OXCT1) plays a crucial role in hepatocellular carcinoma (HCC) progression through its ketolytic and succinyltransferase activities. Despite its potential as a therapeutic target, no small molecules have been developed to inhibit the dual enzymatic activities of OXCT1 specifically. In this study, our structural analysis revealed that the active sites for both enzymatic functions of OXCT1 are located in the same pocket. Targeting this pocket inhibits the binding of OXCT1 to its substrates and blocks both of its enzymatic activities. Thus, we developed two high-throughput screening systems to assess the effects of small molecules on OXCT1's distinct enzymatic activities. By combining these experimental approaches with virtual screening, we identified a compound, D574-0246 (iOXCT1), which effectively inhibits both enzymatic activities. In vitro and in vivo validation demonstrated that iOXCT1 suppresses HCC growth via OXCT1 inhibition. Collectively, our results establish OXCT1 as a promising therapeutic target and identify iOXCT1 as a novel dual-activity inhibitor, providing a foundation for developing OXCT1-targeted therapies against HCC.

Keywords

Hepatocellular carcinoma; High-throughput screening systems; Ketolysis; OXCT1 inhibitor; Succinyltransferase.

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