HuR Confers Resistance of Hepatocellular Carcinoma to Lenvatinib by Inhibiting Ferroptosis

ABSTRACT

This study aim to explore whether human antigen R (HuR) inhibits ferroptosis confers resistance to lenvatinib in hepatocellular carcinoma (HCC). Bioinformatics analysis and immunofluorescence detection of 30 HCC tissue samples were used to verify the clinical correlation between HuR and glutathione peroxidase 4 (GPX4), establish a lenvatinib‐resistant HCC cell line, and evaluate the cell phenotypes and ferroptosis indicators (Fe ²⁺ , reactive oxygen species (ROS), lipid peroxidation, glutathione (GSH)) through functional experiments. The HuR‐GPX4 axis was analysed by genetic intervention methods and verified through xenograft mouse tumour models. Co‐expression of HuR/GPX4 in HCC tissues was associated with poor prognosis. Under lenvatinib treatment, the drug‐resistant cell lines showed increased malignant behaviour and ferroptosis resistance characteristics (decreased ferrous ions, ROS, lipid peroxidation, and increased GSH) in HCC cells, as well as upregulation of lenvatinib targeting vascular endothelial growth factor receptor 1 (VEGFR1)/fibroblast growth factor receptor 3 (FGFR3). HuR promotes the expression of GPX4 via cytoplasmic translocation. Interference with the expression of HuR could reverse the drug resistance phenotype and increase ferroptosis in lenvatinib‐induced HCC; overexpression of GPX4 partially restored drug resistance. HuR is an important molecule for conferring resistance to lenvatinib therapy and may be involved in inhibiting ferroptosis by upregulating the expression and activity of GPX4. This study provides a new strategy for targeting patients with HCC.