beta-Hydroxybutyrate-mediated lysine butyrylation determines therapy response in liver cancer

Hepatocellular carcinoma (HCC) has been a major public health concern worldwide for decades because of its high mortality rates and poor prognosis, which are attributable to frequent tumor relapse and limited treatment strategies. Lenvatinib is one of the tyrosine kinase inhibitors approved for first-line treatment of advanced HCC, but its efficacy remains modest. Growing evidence suggests that the unsatisfactory survival benefits of lenvatinib could be attributed to the acquired drug resistance developed in HCC patients. In this study, we aim to explore the intrinsic metabolic vulnerability which could be exploited to enhance the treatment efficacy of lenvatinib in HCC. Metabolomic profiling of lenvatinib-resistant HCC mouse models revealed significant alterations in the butanoate metabolism pathway, with beta-hydroxybutyrate (BHB) identified as the most deregulated metabolite. Functional assays demonstrated that BHB treatment inhibited HCC cell proliferation and synergistically enhanced lenvatinib-induced apoptosis. Consistent with in vitro findings, BHB administration in HCC patient-derived xenograft models produced synergistic tumor-suppressive effects with lenvatinib. Combination treatment of lenvatinib and ketogenic diet which induces BHB level could drastically attenuate tumor development in mice bearing tumors. This study presents a potentially translatable combination treatment strategy to potentiate the therapeutic efficacy of lenvatinib in advanced HCC.