Yibin Zhang, Yucong Lin, He Cai, Tongchong Zhou
BACKGROUND: Lenvatinib resistance significantly limits treatment efficacy in hepatocellular carcinoma (HCC), yet the underlying mechanisms remain poorly understood. This study investigates the role of EZH2 in mediating lenvatinib resistance through ferroptosis regulation, aiming to identify novel therapeutic targets for overcoming drug resistance in HCC. METHODS: EZH2 expression patterns were analyzed using TCGA datasets and validated in clinical HCC samples through RT-qPCR. Lenvatinib-resistant HCC cell lines were established to examine EZH2's functional role. The impact of EZH2 on ferroptosis was evaluated by measuring cell proliferation, reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) levels. Mechanistic investigations were performed using EZH2 knockdown, ACSL1 expression analysis, and H3K27me3 modification assays. The therapeutic potential of EZH2 inhibition was further assessed in xenograft models. RESULTS: EZH2 was significantly overexpressed in HCC tissues and correlated with poor patient survival. Resistant cell models demonstrated EZH2-mediated suppression of ferroptosis through ACSL1 downregulation via H3K27me3, evidenced by altered ROS, MDA and GSH levels. Genetic inhibition of EZH2 restored lenvatinib sensitivity by upregulating ACSL1 and promoting ferroptosis. In vivo studies confirmed that EZH2 targeting enhanced lenvatinib's antitumor effects in resistant HCC models. CONCLUSIONS: Our findings establish EZH2 as a critical regulator of lenvatinib resistance in HCC through ACSL1-mediated ferroptosis suppression. The EZH2-H3K27me3-ACSL1 axis represents a promising therapeutic target for overcoming drug resistance, offering new strategies to improve HCC treatment outcomes.