BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma

  • Cell Rep Med. 2026 May 19;7(5):102784. doi: 10.1016/j.xcrm.2026.102784.
Misty Shuo Zhang  1 ,  Kenneth Kin-Leung Kwan  2 ,  Aki Pui-Wah Tse  2 ,  Gengchao Wang  3 ,  Larry Lai Wei  3 ,  Kejie Sun  4 ,  Noreen Nog-Qin Chui  3 ,  Derek Lee  2 ,  Macus Hao-Ran Bao  2 ,  Xiaoxuan Pang  4 ,  Zhenqi Wu  4 ,  Yanyan Chen  5 ,  Yangyang Wang  4 ,  Zifan Yang  4 ,  Xue Jiang  2 ,  Qidong Li  2 ,  Yan Zhang  2 ,  Yajie Zhong  2 ,  Jacinth Wing-Sum Cheu  2 ,  Yiling Chen  2 ,  Weixing Li  6 ,  Chun-Ming Wong  3 ,  Jianing Wang  5 ,  Zongwei Cai  5 ,  Qi Zhang  7 ,  Tingbo Liang  7 ,  Irene Oi-Lin Ng  3 ,  Adonia E Papathanassiu  6 ,  Carmen Chak-Lui Wong  8
Affiliations
  • 1. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China; MOE Joint International Research Laboratory of Pancreatic Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, P.R. China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, P.R. China; Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, P.R. China. Electronic address: [email protected].
  • 2. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, P.R. China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, P.R. China.
  • 3. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, P.R. China.
  • 4. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China; MOE Joint International Research Laboratory of Pancreatic Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China.
  • 5. State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, P.R. China.
  • 6. Ergon Pharmaceuticals, LLC, P.O. Box 1001, Silver Spring MD 20910, USA.
  • 7. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China; MOE Joint International Research Laboratory of Pancreatic Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China; Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P.R. China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 8. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China; Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, P.R. China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, P.R. China; Department of Clinical Oncology, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, P.R. China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, Guangdong, P.R. China; Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, P.R. China. Electronic address: [email protected].
PMID: 42061407 DOI: 10.1016/j.xcrm.2026.102784
Abstract

Hypoxia is a common characteristic of solid tumors, especially in hepatocellular carcinoma (HCC). Hypoxia-inducible factors (HIFs), particularly HIF-1α, mediate metabolic adaptation, which is crucial for survival of hypoxic cells. Branched-chain amino transferase 1 (BCAT1) catalyzes the reversible transamination reaction between branched-chain Amino acids (BCAAs) and branched-chain keto acids (BCKAs), involving the inter-conversion of α-ketoglutarate (α-KG) and glutamate. We investigate and delineate the mechanisms by which BCAT1 consumes α-KG and stabilizes HIF-1α, suppressing α-KG-dependent oxygen dehydrogenase, prolyl hydroxylase-domain protein (PHD), inducing HIF-1α-mediated metabolic reprogramming and promoting hypoxic survival of HCC. We evaluate the potency of a BCAT1 inhibitor, ERG245, as a single or combination treatment with tyrosine kinase inhibitor (TKI) in vivo. We further validate the over-expression and correlation of BCAT1 and HIF-1α downstream metabolic genes in HCC clinical samples. Our results indicate that BCAT1 benefits HCC growth through HIF-1α-induced metabolic reprogramming. Targeting BCAT1 will provide an effective therapeutic strategy for HCC patients.

Keywords
EGR245; branched-chain amino transferase 1; hepatocellular carcinoma; hypoxia; hypoxia-inducible factor; metabolic reprogramming; prolyl hydroxylase-domain protein; α-ketoglutarate.
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