EP1 activation inhibits doxorubicin-cardiomyocyte ferroptosis via Nrf2

• Published in: Redox biology Vol. 65; p. 102825
• Main Authors: Wang, Bei, Jin, Yuxuan, Liu, Jiao, Liu, Qian, Shen, Yujun, Zuo, Shengkai, Yu, Ying
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2023; Elsevier
• Subjects: Cardiomyocyte ferroptosis; DOX-induced cardiomyopathy; EP1; Nrf2; Research Paper; Cardiomyocyte ferroptosis; DOX-induced cardiomyopathy; Nrf2; EP1
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2023.102825

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.