化疗药物，如多柔比星（DOX），可能导致心肌病，甚至危及生命的心律失常。铁依赖型氧化性编程性细胞死亡形式——铁死亡，在多柔比星诱导的心肌病（DIC）中发挥关键作用。前列腺素（PG）是生物活性信号分子，在生理和病理条件下深刻调节心脏功能。在这里，我们发现环氧前列腺素1（E-prostanoid 1 receptor，EP1）受体上调，导致前列腺素E2（PGE2）的产生也上调，在铁死亡诱导剂厄拉斯汀（erastin）或多柔比星处理的心肌细胞中。EP1抑制剂显著加重厄拉斯汀或多柔比星诱导的心肌细胞的铁死亡，而EP1激活则起相反的效果。在心肌细胞中遗传性缺失EP1加重了多柔比星诱导的小鼠心脏损伤，而铁死亡抑制剂铁止痛素-1（Ferrostatin-1，Fer-1）能有效挽救。在机制上，EP1的激活通过促进抗氧化基因核因子红细胞2相关因子2（nuclear factor erythroid 2-related factor 2，Nrf2）的表达，如谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4）和溶质载体家族成员11（solute carrier family 7 member 11，SLC7A11），保护心肌细胞免受多柔比星诱导的铁死亡。在铁死亡心肌细胞中，EP1通过Gαq耦联，引发细胞内Ca2+通量，激活PKC/Nrf2级联反应。EP1激活还可防止多柔比星诱导的人类心肌细胞的铁死亡。因此，PGE2/EP1轴通过激活PKC/Nrf2信号传导保护心肌细胞免受DOX诱导的铁死亡，EP1的激活可能成为DIC预防和治疗的一种有吸引力的策略。版权所有©2023年作者.由Elsevier B.V.出版.版权所有.

Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent oxidative form of programmed necrosis, plays a pivotal role in DOX-induced cardiomyopathy (DIC). Prostaglandins (PGs) are bioactive signaling molecules that profoundly modulate cardiac performance in both physiologic and pathologic conditions. Here, we found that PGE2 production and its E-prostanoid 1 receptor (EP1) expression were upregulated in erastin (a ferroptosis inducer) or DOX-treated cardiomyocytes. EP1 inhibition markedly aggravated erastin or DOX-induced cardiomyocyte ferroptosis, whereas EP1 activation exerted opposite effect. Genetic depletion of EP1 in cardiomyocytes worsens DOX-induced cardiac injury in mice, which was efficiently rescued by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Mechanistically, EP1 activation protected cardiomyocytes from DOX-induced ferroptosis by promoting nuclear factor erythroid 2-related factor 2 (Nrf2)-driven anti-oxidative gene expression, such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). EP1 was coupled with Gαq to elicit intracellular Ca2+ flux and activate the PKC/Nrf2 cascade in ferroptotic cardiomyocytes. EP1 activation also prevents DOX-induced ferroptosis in human cardiomyocytes. Thus, PGE2/EP1 axis protects cardiomyocytes from DOX-induced ferroptosis by activating PKC/Nrf2 signaling and activation of EP1 may represent an attractive strategy for DIC prevention and treatment.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.