TY - JOUR
T1 - BCAT1-dependent HIF-1α stabilization is a targetable metabolic vulnerability in hepatocellular carcinoma
AU - Zhang, Misty Shuo
AU - Kwan, Kenneth Kin-Leung
AU - Tse, Aki Pui-Wah
AU - Wang, Gengchao
AU - Wei, Larry Lai
AU - Sun, Kejie
AU - Chui, Noreen Nog-Qin
AU - Lee, Derek
AU - Bao, Macus Hao-Ran
AU - Pang, Xiaoxuan
AU - Wu, Zhenqi
AU - Chen, Yanyan
AU - Wang, Yangyang
AU - Yang, Zifan
AU - Jiang, Xue
AU - Li, Qidong
AU - Zhang, Yan
AU - Zhong, Yajie
AU - Cheu, Jacinth Wing-Sum
AU - Chen, Yiling
AU - Li, Weixing
AU - Wong, Chun-Ming
AU - Wang, Jianing
AU - Cai, Zongwei
AU - Zhang, Qi
AU - Liang, Tingbo
AU - Ng, Irene Oi-Lin
AU - Papathanassiu, Adonia E.
AU - Wong, Carmen Chak-Lui
N1 - Publisher Copyright:
© 2026 The Authors. Published by Elsevier Inc.
Funding Information:
This study is supported by NSFC General Program (82173123, C.C.-L.W.), RGC CRF (C7008-22G and C5016-23G, C.C.-L.W.), RGC TBRS (T12-716/22-R, C.C.-L.W. and I.O.-L.N.), RGC RIF (R5008-22, C.C.-L.W.), NSFC Distinguished Young Scholars Fund (82425043, C.C.-L.W.), The Centre for Oncology and Immunology under the Health@InnoHK (C.C.-L.W.), The University of Hong Kong Outstanding Research Supervisor Award (C.C.-L.W.), Shenzhen Science and Technology Program (ZDSYS20210623091811035, C.C.-L.W.), RGC RFS2024 (RFS24 25-7S01, C.C.-L.W.), NSFC Youth Program (82103196, M.S.Z.), and Investigator Start-up Funds of the FAHZU (BQD2303, M.S.Z.).
PY - 2026/5/19
Y1 - 2026/5/19
N2 - 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.
AB - 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.
KW - EGR245
KW - branched-chain amino transferase 1
KW - hepatocellular carcinoma
KW - hypoxia
KW - hypoxia-inducible factor
KW - metabolic reprogramming
KW - prolyl hydroxylase-domain protein
KW - α-ketoglutarate
UR - https://www.scopus.com/pages/publications/105039135215
U2 - 10.1016/j.xcrm.2026.102784
DO - 10.1016/j.xcrm.2026.102784
M3 - Journal article
C2 - 42061407
SN - 2666-3791
VL - 7
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 5
M1 - 102784
ER -
SDG 3 Good Health and Well-being