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

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-catenin^S33Y-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-catenin^S33Y-mutated HCC exhibited ketogenic therapy resistance and increased metastasis. Mechanistically, mutated β-catenin^S33Y 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-catenin^S33Y-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-catenin^S33Y-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-catenin^S33Y-mutated HCC.