Lenvatinib triggers an EGR1-ZNF768-SLC7A11 adaptive response to limit ferroptosis-mediated therapeutic efficacy in hepatocellular carcinoma

OBJECTIVE: Adaptive therapeutic tolerance frequently limits first-line lenvatinib efficacy in hepatocellular carcinoma (HCC). This study explored the C2H2-type zinc finger (ZNF) protein family (the largest class of transcription factors) and hypothesized that specific members of the ZNF protein family are hijacked by cancer cells to orchestrate pro-survival defenses against lenvatinib-induced ferroptosis. METHODS: . RESULTS: . CONCLUSIONS: The EGR1-ZNF768-SLC7A11 axis constitutes a critical adaptive shield limiting lenvatinib efficacy in HCC. ZNF768 serves as a predictive biomarker and a high-value therapeutic target. Disrupting this axis offers a rational strategy to overcome therapeutic resistance and maximize the clinical potential of lenvatinib.