Ferroptosis, a regulated form of cell death triggered by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for cancer treatment, particularly in hepatocellular carcinoma (HCC). However, the mechanisms underlying the regulation of ferroptosis in HCC remain to be unclear. In this study, we have identified a novel regulatory pathway of ferroptosis involving the inhibition of Apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme with dual functions in DNA repair and redox regulation. Our findings demonstrate that inhibition of APE1 leads to the accumulation of lipid peroxidation and enhances ferroptosis in HCC. At the molecular level, the inhibition of APE1 enhances ferroptosis which relies on the redox activity of APE1 through the regulation of the NRF2/SLC7A11/GPX4 axis. We have identified that both genetic and chemical inhibition of APE1 increases AKT oxidation, resulting in an impairment of AKT phosphorylation and activation, which leads to the dephosphorylation and activation of GSK3β, facilitating the subsequent ubiquitin-proteasome-dependent degradation of NRF2. Consequently, the downregulation of NRF2 suppresses SLC7A11 and GPX4 expression, triggering ferroptosis in HCC cells and providing a potential therapeutic approach for ferroptosis-based therapy in HCC. Overall, our study uncovers a novel role and mechanism of APE1 in the regulation of ferroptosis and highlights the potential of targeting APE1 as a promising therapeutic strategy for HCC and other cancers.

铁死亡是一种由铁依赖性脂质过氧化引发的细胞死亡的调节形式，已成为一种有前景的癌症治疗策略，特别是在肝细胞癌 (HCC) 中。然而，HCC 铁死亡调节的机制仍不清楚。在这项研究中，我们发现了一种新的铁死亡调节途径，涉及抑制无嘌呤/无嘧啶核酸内切酶 1 (APE1)，这是一种在 DNA 修复和氧化还原调节中具有双重功能的关键酶。我们的研究结果表明，抑制 APE1 会导致脂质过氧化的积累并增强 HCC 中的铁死亡。在分子水平上，抑制 APE1 可增强铁死亡，铁死亡依赖于 APE1 通过调节 NRF2/SLC7A11/GPX4 轴的氧化还原活性。我们发现，APE1 的遗传和化学抑制都会增加 AKT 氧化，导致 AKT 磷酸化和激活受损，从而导致 GSK3β 去磷酸化和激活，促进随后泛素蛋白酶体依赖性 NRF2 降解。因此，NRF2 的下调会抑制 SLC7A11 和 GPX4 的表达，引发 HCC 细胞的铁死亡，并为 HCC 中基于铁死亡的治疗提供潜在的治疗方法。总的来说，我们的研究揭示了 APE1 在铁死亡调节中的新作用和机制，并强调了靶向 APE1 作为 HCC 和其他癌症的有前途的治疗策略的潜力。