β-catenin mutation reprograms ketone body metabolism to drive hepatocellular carcinoma metastasis and resistance to ketogenic therapy via transcriptional activation of OXCT1

  • Cell Death Dis. 2026 Mar 9;17(1):301. doi: 10.1038/s41419-026-08457-y.
Huan Li  #  1 ,  Liyuan Qian  #  2 ,  Yifan Ji  #  1 ,  Yuanhao Geng  1 ,  Yanjun Lu  3 ,  Laizhu Zhang  1 ,  Yanchao Xu  1 ,  Weiwei Zong  3 ,  Xiang Jiang  1 ,  Xianwei Zhou  1 ,  Jingyuan Wen  1 ,  Donglin Liu  1 ,  Ye Wang  1 ,  Yunzheng Li  1 ,  Binghua Li  4 ,  Hucheng Ma  5 ,  Decai Yu  6  7
Affiliations
  • 1. State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 2. Department of Hepatobiliary and Pancreatic Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China.
  • 3. Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
  • 4. State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. [email protected].
  • 5. State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. [email protected].
  • 6. State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. [email protected].
  • 7. Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 41803092 DOI: 10.1038/s41419-026-08457-y
Abstract

The ketogenic diet is a controversial approach to Cancer therapy. Over 30% of hepatocellular carcinoma (HCC) cases harbor β-catenin activating mutations, among which the S33Y mutation represents a classical hotspot conferring constitutive pathway activation. Our previous metabolic profiling predicted that β-catenin-mutated HCC may exhibit intrinsic resistance to ketogenic therapy. 3-oxoacid CoA-transferase 1 (OXCT1), the key enzyme for ketone body catabolism, is aberrantly expressed in β-catenin-mutated HCC. This study explores how β-cateninS33Y-mutated HCC activates OXCT1 to reprogram ketone body metabolism to drive HCC ketogenic therapy resistance and metastasis. Utilizing subcutaneous tumor models and patient-derived xenograft (PDX) models of HCC, we demonstrated that ketogenic treatment was effective in β-catenin-wild-type HCC, whereas β-cateninS33Y-mutated HCC exhibited ketogenic therapy resistance and increased metastasis. Mechanistically, mutated β-cateninS33Y bound the transcription factor LEF1, which activated OXCT1 to promote ketolysis. An isotope metabolic flux experiment with C13-labeled β-hydroxybutyrate confirmed that β-catenin-activated OXCT1 converts ketone bodies into glutamate. Blocking OXCT1 in β-cateninS33Y-mutated HCC abolished resistance to ketogenic therapy and reduced tumor glutamate levels. Furthermore, OXCT1, activated by mutated β-catenin, enhanced HCC metastasis via the p-STAT3 and epithelial-mesenchymal transition pathways. Inhibition of OXCT1 attenuated its promoting effect on metastasis. Overall, in β-cateninS33Y-mutated HCC, OXCT1 activation leads to metabolic reprogramming of ketone bodies, resulting in resistance to ketogenic therapy and promoting metastasis. Targeting OXCT1 represents a promising strategy for treating β-cateninS33Y-mutated HCC.

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