Abstract Lenvatinib, a first-line targeted therapy for advanced hepatocellular carcinoma (HCC), exhibits significant clinical efficacy. At present, there remains a scarcity of effective treatment options for patients experiencing lenvatinib resistance. This study aims to identify and validate molecular markers capable of predicting the therapeutic response of HCC patients to lenvatinib treatment. We successfully established a lenvatinib-resistant hepatocellular carcinoma cell line (Huh7/LR) through progressive exposure of parental Huh7 cells to lenvatinib. Through RNA sequencing (RNA-seq) analysis, ubiquitin-specific protease 43 (USP43) was ultimately pinpointed as a potential key molecule related to lenvatinib resistance. The expression of USP43 is notably elevated in lenvatinib-resistant HCC cells and tissues, correlating with a poor prognosis for HCC. USP43 promotes the proliferation of HCC cells, suppresses apoptosis, and enhances resistance to lenvatinib. Mechanistically, ETS1 transcriptionally upregulates USP43. USP43 then binds to non-muscle myosin heavy chain 9 (MYH9) and removes its K48-linked polyubiquitination. This stabilizes the MYH9 protein by preventing its degradation through the ubiquitin-proteasome pathway and further activates the AKT/BAD signaling axis, ultimately suppressing apoptosis and conferring lenvatinib resistance. Implications: Targeting the ETS1/USP43/MYH9 axis presents a promising therapeutic strategy to overcome lenvatinib resistance in HCC.
Chen et al. (2026) studied this question.