This study investigates the role of Apurinic/apyrimidinic endonuclease 1 (APE1) in ferroptosis, a regulated form of cell death triggered by iron-dependent lipid peroxidation, in hepatocellular carcinoma (HCC). The authors found that inhibiting APE1 enhances ferroptosis in HCC cells by increasing lipid peroxidation and reactive oxygen species (ROS) levels. Mechanistically, APE1 inhibition downregulates the transcription factor NRF2, which is crucial for maintaining the expression of SLC7A11 and GPX4, key regulators of ferroptosis. This downregulation of NRF2 is mediated through the AKT/GSK3β pathway, where APE1 affects the redox state of AKT, leading to its impaired phosphorylation and activation. The study also demonstrates that APE1 inhibition enhances the sensitivity of HCC to ferroptosis in an in vivo xenograft model and that APE1 expression is associated with the progression and prognosis of HCC. Overall, the findings suggest that targeting APE1 could be a promising therapeutic strategy for HCC and other cancers.This study investigates the role of Apurinic/apyrimidinic endonuclease 1 (APE1) in ferroptosis, a regulated form of cell death triggered by iron-dependent lipid peroxidation, in hepatocellular carcinoma (HCC). The authors found that inhibiting APE1 enhances ferroptosis in HCC cells by increasing lipid peroxidation and reactive oxygen species (ROS) levels. Mechanistically, APE1 inhibition downregulates the transcription factor NRF2, which is crucial for maintaining the expression of SLC7A11 and GPX4, key regulators of ferroptosis. This downregulation of NRF2 is mediated through the AKT/GSK3β pathway, where APE1 affects the redox state of AKT, leading to its impaired phosphorylation and activation. The study also demonstrates that APE1 inhibition enhances the sensitivity of HCC to ferroptosis in an in vivo xenograft model and that APE1 expression is associated with the progression and prognosis of HCC. Overall, the findings suggest that targeting APE1 could be a promising therapeutic strategy for HCC and other cancers.