ArticleCell reports. Medicine2026
BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma.
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29 authors.
Misty Shuo ZhangZhejiang 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: mistyzs@zju.edu.cn.
Kenneth Kin-Leung KwanDepartment 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.
Aki Pui-Wah TseDepartment 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.
Gengchao WangDepartment 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.
Larry Lai WeiDepartment 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.
Kejie SunZhejiang 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.
Noreen Nog-Qin ChuiDepartment 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.
Derek LeeDepartment 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.
Macus Hao-Ran BaoDepartment 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.
Xiaoxuan PangZhejiang 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.
Zhenqi WuZhejiang 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.
Yanyan ChenState Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, P.R. China.
Yangyang WangZhejiang 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.
Zifan YangZhejiang 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.
Xue JiangDepartment 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.
Qidong LiDepartment 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.
Yan ZhangDepartment 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.
Yajie ZhongDepartment 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.
Jacinth Wing-Sum CheuDepartment 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.
Yiling ChenDepartment 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.
Weixing LiErgon Pharmaceuticals, LLC, P.O. Box 1001, Silver Spring MD 20910, USA.
Chun-Ming WongDepartment 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.
Jianing WangState Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, P.R. China.
Zongwei CaiState Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong SAR, P.R. China.
Qi ZhangZhejiang 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.
Tingbo LiangZhejiang 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.
Irene Oi-Lin NgDepartment 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.
Adonia E PapathanassiuErgon Pharmaceuticals, LLC, P.O. Box 1001, Silver Spring MD 20910, USA.
Carmen Chak-Lui WongDepartment 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: carmencl@pathology.hku.hk.
Funding
No grant is acknowledged in the PubMed record.
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.
Indexed as
Carcinoma, HepatocellularHypoxia-Inducible Factor 1, alpha SubunitLiver NeoplasmsTransaminasesAnimalsCell Line, TumorGene Expression Regulation, NeoplasticHumansKetoglutaric AcidsMetabolic ReprogrammingMiceBCAT1 protein, humanHIF1A protein, humanHypoxia-Inducible Factor 1, alpha SubunitKetoglutaric AcidsTransaminasesbranched-chain amino transferase 1EGR245hepatocellular carcinomahypoxiahypoxia-inducible factormetabolic reprogrammingprolyl hydroxylase-domain proteinα-ketoglutarate
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