The RBMS1–SLC7A11 axis regulates ferroptosis susceptibility and lenvatinib sensitivity in hepatocellular carcinoma

Hepatocellular carcinoma remains a leading cause of cancer-related mortality worldwide. Although lenvatinib is widely deployed as a frontline systemic therapy for advanced disease, its clinical utility is frequently subverted by primary or adaptive non-responsiveness. Evasion of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key survival mechanism for tumor cells under therapeutic stress. While the RNA-binding protein RBMS1 is known to participate in oncogenic progression and ferroptotic regulation across several malignancies, whether it modulates lenvatinib sensitivity in hepatocellular carcinoma by intersecting with the SLC7A11-dependent antioxidant pathway has not been established. Expression profiles of RBMS1 and SLC7A11 were interrogated in paired clinical tissue samples and public transcriptomic datasets. Stable lentiviral overexpression or short hairpin RNA-mediated knockdown was executed in HepG2 and Huh7 cells to modulate candidate gene abundance. Cellular phenotypes, comprising viability, clonogenicity, migration, invasion, and drug sensitivity, were mapped via cell counting kit-eight, colony formation, wound healing, and transwell migration assays. Ferroptotic kinetics and oxidative shifts were tracked by measuring intracellular reactive oxygen species and lipid peroxidation using fluorescent probes. Finally, a subcutaneous xenograft model was established to validate the synergistic potential of RBMS1 depletion with lenvatinib therapy in vivo. In clinical specimens, SLC7A11 was markedly upregulated and tied to shortened overall survival, while RBMS1 expression exhibited a strong upward trend that correlated robustly with SLC7A11 abundance in broader transcriptomic cohorts. Functionally, overexpressing RBMS1 accelerated malignant behaviors, expanded SLC7A11 protein levels, neutralized reactive oxygen species, and shielded cells from lipid peroxidation, ultimately lowering lenvatinib sensitivity. Conversely, silencing RBMS1 yielded opposite phenotypes, aggravating ferroptotic oxidative damage and amplifying lenvatinib responsiveness. Epistatic rescue experiments demonstrated that SLC7A11 knockdown completely abrogated the anti-ferroptotic defense and drug tolerance conferred by RBMS1 hyperactivation. In vivo animal models corroborated these dynamics, showing that RBMS1 knockdown significantly potentiated the antitumor efficacy of lenvatinib. These findings position RBMS1 as a novel upstream post-transcriptional regulator of SLC7A11-dependent ferroptosis susceptibility and lenvatinib responsiveness in hepatocellular carcinoma. By reinforcing the SLC7A11 antioxidant network, RBMS1 shields malignant cells from drug-induced oxidative catastrophe. Targeting this newly uncovered post-transcriptional axis represents a viable therapeutic strategy to overcome lenvatinib tolerance in advanced disease.