USP10 confers lenvatinib resistance in hepatocellular carcinoma by deubiquitinating the GPX2

Lenvatinib is a first-line treatment for advanced hepatocellular carcinoma (HCC), yet the development of resistance constitutes a major therapeutic obstacle. While Ubiquitin-specific peptidase 10 (USP10) has been implicated in cancer progression, its specific role in lenvatinib resistance remains unclear. Using lentiviral transduction, we established HCC cell lines with stable USP10 overexpression or knockdown. The role of USP10 was further investigated using the selective inhibitor Spautin-1. Cell viability and proliferation were assessed via CCK-8 and colony formation assays. Apoptosis and reactive oxygen species (ROS) levels were measured. A xenograft mouse model was generated by subcutaneously injecting PLC/8024 cells into nude mice to evaluate tumor growth and drug response in vivo. Mechanistic insights were gained through co-immunoprecipitation, ubiquitination assays, RNA sequencing, and bioinformatics analysis. We identified USP10 as a critical driver of lenvatinib resistance in HCC. Genetic silencing or pharmacological inhibition of USP10 suppressed tumor growth and restored lenvatinib sensitivity both in vitro and in vivo. Mechanistically, USP10 directly binds to and deubiquitinates glutathione peroxidase 2 (GPX2), enhancing its protein stability. This USP10/GPX2 axis scavenges intracellular ROS, thereby inhibiting apoptosis and promoting HCC cell survival and proliferation under lenvatinib treatment. Our findings reveal a novel USP10/GPX2 signaling pathway that confers lenvatinib resistance in HCC by mitigating oxidative stress. Targeting USP10 presents a promising therapeutic strategy to overcome resistance and improve outcomes for patients with advanced HCC.