铁过氧化物酶死（Ferroptosis）是一种遗传学和生化学上与众不同的程序性细胞死亡形式，其特点是铁依赖性脂质过氧化物的积累。治疗耐药的肿瘤细胞对铁过氧化物酶死表现出易感性。内质网（ER）应激和未折叠蛋白应激（UPR）在肿瘤细胞中发挥着关键作用，使其能够变得抗药。调节UPR平衡以使癌细胞易受铁过氧化物酶性细胞死亡攻击可能是一种有吸引力的治疗策略。为了解内质网应激在铁过氧化物酶死过程中的新兴贡献，我们观察到铁过氧化物酶诱导剂RSL3促进了UPR（PERK，ATF6和IRE1α）的活化，以及半胱氨酸-谷氨酸转运蛋白SLC7A11（Xc-系统）的过表达。通过探索特定的UPR分支在调节SLC7A11表达和随后的铁过氧化物酶死过程中的作用，我们发现PERK在诱导结肠直肠癌细胞发生铁过氧化物酶死中具有选择性的关键作用。PERK的抑制减少了ATF4的表达，并降低了其对SLC7A11启动子的结合，导致SLC7A11的下调。PERK功能的丧失不仅为癌细胞增加了脂质过氧化，还限制了体内结肠直肠肿瘤的生长，显示出原位活跃的铁过氧化物酶性细胞死亡迹象。此外，通过进行TCGA数据挖掘并使用结肠直肠癌患者样本，我们证明PERK和SLC7A11的表达呈正相关。总体而言，我们的实验数据表明PERK是铁过氧化物酶死的负调控因子，PERK功能的丧失使结肠直肠癌细胞对铁过氧化物酶死变得敏感。因此，小分子PERK抑制剂作为新型治疗药物具有巨大的潜力，并且可以针对抗凋亡耐药状态的应用。Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1α), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.