Targeting CPT1A-mediated fatty acid oxidation sensitizes hepatocellular carcinoma to lenvatinib

Lenvatinib is a first-line therapeutic agent for patients with unresectable hepatocellular carcinoma (HCC). However, the limited durability of response and adaptive therapeutic escape significantly compromise its long-term effectiveness. Lenvatinib exerts its antitumor effects primarily through the inhibition of angiogenesis; nevertheless, the mechanisms by which HCC cells evade antiangiogenic therapy in vivo remain unclear. Orthotopic liver tumor models and tandem mass tag (TMT)-based quantitative proteomics were employed to identify dysregulated proteins in lenvatinib-treated tumors. Specific inhibitors or shRNA-mediated gene knockdown were utilized to validate the role of fatty acid oxidation (FAO) in mediating the adaptive survival of HCC under lenvatinib treatment. To elucidate the underlying mechanisms, we performed immunohistochemistry (IHC), western blotting, Oil Red O (ORO) staining, TUNEL staining, EdU staining, real-time quantitative PCR (RT-qPCR), chromatin immunoprecipitation (ChIP), CCK-8 assays, and flow cytometry analysis of apoptosis. Furthermore, glucose levels, adenosine triphosphate (ATP) levels and FAO activity were measured. Tumor tissues from HCC patients treated with or without lenvatinib were analyzed for protein levels via IHC. Through integrated analysis of orthotopic liver tumor models and quantitative proteomics, we demonstrated that lenvatinib treatment significantly depleted intratumoral glucose levels, activated the FAO pathway, and reduced lipid droplet accumulation in HCC cells. Critically, while pharmacological or genetic inhibition of carnitine palmitoyltransferase 1 A (CPT1A)—the rate-limiting enzyme of FAO—alone failed to suppress tumor growth, its combination with lenvatinib synergistically enhanced antitumor efficacy in vivo. Consistent with the in vivo observations, CPT1A inhibition attenuated FAO activity and depleted ATP, leading to suppressed proliferation and increased death in glucose-deprived HCC cells in vitro. Mechanistically, lenvatinib-induced glucose deficiency triggered CPT1A transcription via activation of the ERK/c-Jun signaling axis, thereby increasing FAO activity, decreasing lipid storage, and replenishing intracellular ATP levels in HCC cells under glucose-deficient conditions. Furthermore, comparative analysis of clinical specimens revealed significantly lower CPT1A expression in tumor tissues from lenvatinib-sensitive HCC patients than in those from untreated controls. Our findings underscore the critical role of FAO as a specific adaptive response to lenvatinib-induced metabolic stress, indicating that targeting CPT1A represents a promising strategy to sensitize HCC to lenvatinib. Lenvatinib inhibits tumor angiogenesis, inducing intratumoral glucose deprivation. This scarcity activates the ERK/c-Jun pathway, upregulating CPT1A to enhance FAO. Consequently, FAO activation reduces lipid droplets and replenishes ATP levels under glucose deficiency, sustaining tumor cell survival. Targeting CPT1A-mediated FAO represents a promising strategy to sensitize HCC to lenvatinib