LARS inhibition overcomes regorafenib resistance in hepatocellular carcinoma via ferroptosis and drug metabolism

BACKGROUND: Regorafenib improves outcomes in advanced hepatocellular carcinoma (HCC), but acquired resistance limits its durable therapeutic benefit. The metabolic and redox mechanisms driving regorafenib resistance remain incompletely defined. METHODS: -) models were generated by long-term stepwise drug exposure. Transcriptomic profiling, LC-MS/MS, Seahorse extracellular flux analysis, ferroptosis-related assays, and apoptosis assays were used to characterize resistance-associated alterations. LARS1 was modulated by shRNA knockdown, overexpression, and pharmacological inhibition using BC-LI-0186. Therapeutic efficacy was evaluated in vitro and in Regᴿ Huh7 xenografts. Clinical relevance was assessed using paired HCC specimens, clinicopathological analysis, TCGA-LIHC, and TNMplot datasets. RESULTS: , suppressed GPX4/SLC7A11 expression, increased lipid ROS and apoptosis, and disrupted the hypermetabolic phenotype of Regᴿ cells by reducing both OCR and ECAR. In xenograft models, combined regorafenib and BC-LI-0186 treatment produced the strongest tumor growth inhibition and reduced LARS1/GPX4 expression, although body-weight monitoring indicated the need for toxicity evaluation. CONCLUSIONS: LARS1 acts as a druggable metabolic regulator that links regorafenib biotransformation, mTOR-related metabolic adaptation, and GPX4/SLC7A11-mediated ferroptosis defense in resistant HCC. Targeting LARS1 with BC-LI-0186 may restore regorafenib sensitivity and represents a potential strategy for overcoming acquired regorafenib resistance.