Nghiem Thu-Hang Thi, Nguyen Kim Anh, Kusuma Fedho, Park Soyoung, Park Jeongmin, Joe Yeonsoo, Han Jaeseok, Chung Hun Taeg
Department of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea.
Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea.
Antioxidants (Basel). 2025 Mar 3;14(3):307. doi: 10.3390/antiox14030307.
Ferroptosis, a regulated form of cell death characterized by lipid peroxidation and iron accumulation, is increasingly recognized for its role in disease pathogenesis. The unfolded protein response (UPR) has been implicated in both endoplasmic reticulum (ER) stress and ferroptosis-mediated cell fate decisions; yet, the specific mechanism remains poorly understood. In this study, we demonstrated that ER stress induced by tunicamycin and ferroptosis triggered by erastin both activate the UPR, leading to the induction of ferroptotic cell death. This cell death was mitigated by the application of chemical chaperones and a ferroptosis inhibitor. Among the three arms of the UPR, the PERK-eIF2α-ATF4 signaling axis was identified as a crucial mediator in this process. Mechanistically, the ATF4-driven induction of DDIT4 plays a pivotal role, facilitating ferroptosis via the inhibition of the mTORC1 pathway. Furthermore, acetaminophen (APAP)-induced hepatotoxicity was investigated as a model of eIF2α-ATF4-mediated ferroptosis. Our findings reveal that the inhibition of eIF2α-ATF4 or ferroptosis protects against APAP-induced liver damage, underscoring the therapeutic potential of targeting these pathways. Overall, this study not only clarifies the intricate role of the PERK-eIF2α-ATF4 axis in ER-stress-and erastin-induced ferroptosis but also extends these findings to a clinically relevant model, providing a foundation for potential therapeutic interventions in conditions characterized by dysregulated ferroptosis and ER stress.
铁死亡是一种由脂质过氧化和铁积累所表征的受调控的细胞死亡形式，其在疾病发病机制中的作用日益受到认可。未折叠蛋白反应（UPR）与内质网（ER）应激和铁死亡介导的细胞命运决定均有关联；然而，具体机制仍知之甚少。在本研究中，我们证明了衣霉素诱导的ER应激和埃拉斯汀引发的铁死亡均激活UPR，导致铁死亡性细胞死亡的诱导。通过应用化学伴侣和铁死亡抑制剂可减轻这种细胞死亡。在UPR的三个分支中，PERK-eIF2α-ATF4信号轴被确定为这一过程中的关键介质。从机制上讲，ATF4驱动的DDIT4诱导起关键作用，通过抑制mTORC1途径促进铁死亡。此外，对乙酰氨基酚（APAP）诱导的肝毒性作为eIF2α-ATF4介导的铁死亡模型进行了研究。我们的研究结果表明，抑制eIF2α-ATF4或铁死亡可预防APAP诱导的肝损伤，突出了靶向这些途径的治疗潜力。总体而言，本研究不仅阐明了PERK-eIF2α-ATF4轴在ER应激和埃拉斯汀诱导的铁死亡中的复杂作用，还将这些发现扩展到一个临床相关模型，为以铁死亡和ER应激失调为特征的疾病的潜在治疗干预提供了基础。
