Enolase 1 inhibition potentiates sorafenib efficacy in hepatocellular carcinoma through ferroptosis induction.

Abstract

Enolase 1 (ENO1) is overexpressed in hepatocellular carcinoma (HCC) and correlates with poor patient prognosis, as evidenced by TCGA and Kaplan-Meier (KM) analysis. This study demonstrates that targeting ENO1 with its specific inhibitor, ENOblock, markedly enhances the antitumor efficacy of sorafenib in HCC cells. The combination of sorafenib and ENOblock significantly suppresses cell proliferation, migration, invasion, and angiogenesis in vitro and in vivo. Mechanistically, sorafenib and ENOblock synergistically promote ferroptosis by concurrently regulating the Keap1/Nrf2/NQO1 and TFR1/C-MYC/NCOA4/FTH1/LC3 pathways, independent of xCT/GPX4 pathway. These effects are characterized by elevated levels of reactive oxygen species (ROS), iron ions, and malondialdehyde (MDA). In vivo tumorigenic models further confirm that the enhanced therapeutic effect of sorafenib by ENOblock. Our findings not only elucidate a novel ferroptosis-based mechanism underlying sorafenib response in HCC, but also position ENOblock-sorafenib combination as a promising preclinical proof- of-concept strategy targeting ENO1 for HCC intervention.