POLRMT enhances lenvatinib resistance in hepatocellular carcinoma cells by maintaining mitochondrial ATP production

Lenvatinib is one of first-line therapeutic agents for advanced hepatocellular carcinoma (HCC), yet lenvatinib resistance of tumor resulting in a weak response on many patients. Mitochondrial energy metabolism is environmentally adaptable and has been shown to play a crucial role in tumor resistance to therapy. Therefore, identification of the key regulator of mitochondrial energy metabolism during lenvatinib resistance provides a novel target for drug-resistant HCC. We found that POLRMT upregulated in lenvatinib-resistant HCC and is associated with poor patient prognosis. POLRMT increased oxidative phosphorylation levels and mitochondrial ATP production through transcriptional upregulation of respiratory chain complexes, which counteracted lenvatinib-induced cellular ATP decrease and the AMPK-caspase 3 signaling pathway. Furthermore, using IMT1B, a specific inhibitor of POLRMT, resensitized the resistant HCC to lenvatinib in vitro and in vivo. This study highlights the critical role of POLRMT in maintaining mitochondrial ATP production, and suggests that POLRMT could serve as a novel prognostic biomarker and potential therapeutic target for lenvatinib-resistant HCC.