Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for hepatocellular carcinoma (HCC). This study identifies a novel regulatory pathway of ferroptosis involving the inhibition of Apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme with dual roles in DNA repair and redox regulation. Inhibition of APE1 leads to increased lipid peroxidation and enhanced ferroptosis in HCC. At the molecular level, APE1 inhibition enhances ferroptosis through the regulation of the NRF2/SLC7A11/GPX4 axis. Genetic and chemical inhibition of APE1 increases AKT oxidation, impairing AKT phosphorylation and activation, which leads to the dephosphorylation and activation of GSK3β, facilitating the ubiquitin-proteasome-dependent degradation of NRF2. This downregulation of NRF2 suppresses SLC7A11 and GPX4 expression, triggering ferroptosis in HCC cells. The study reveals a novel role of APE1 in ferroptosis regulation and highlights the potential of targeting APE1 as a therapeutic strategy for HCC and other cancers. APE1 inhibition enhances the sensitivity of HCC cells to ferroptosis inducers, promoting ferroptosis in vivo. Clinical data show that APE1, SLC7A11, GPX4, and NRF2 expression is associated with HCC progression and prognosis. The study establishes APE1 as a regulator of ferroptosis and suggests that targeting APE1 to promote ferroptosis may be a promising therapeutic strategy for HCC.Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for hepatocellular carcinoma (HCC). This study identifies a novel regulatory pathway of ferroptosis involving the inhibition of Apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme with dual roles in DNA repair and redox regulation. Inhibition of APE1 leads to increased lipid peroxidation and enhanced ferroptosis in HCC. At the molecular level, APE1 inhibition enhances ferroptosis through the regulation of the NRF2/SLC7A11/GPX4 axis. Genetic and chemical inhibition of APE1 increases AKT oxidation, impairing AKT phosphorylation and activation, which leads to the dephosphorylation and activation of GSK3β, facilitating the ubiquitin-proteasome-dependent degradation of NRF2. This downregulation of NRF2 suppresses SLC7A11 and GPX4 expression, triggering ferroptosis in HCC cells. The study reveals a novel role of APE1 in ferroptosis regulation and highlights the potential of targeting APE1 as a therapeutic strategy for HCC and other cancers. APE1 inhibition enhances the sensitivity of HCC cells to ferroptosis inducers, promoting ferroptosis in vivo. Clinical data show that APE1, SLC7A11, GPX4, and NRF2 expression is associated with HCC progression and prognosis. The study establishes APE1 as a regulator of ferroptosis and suggests that targeting APE1 to promote ferroptosis may be a promising therapeutic strategy for HCC.