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

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

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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