Jeongmin Park , Min Zheng , Jeong Heon Gong , LiHua Jin , Stefan W. Ryter , Yeonsoo Joe , Hun Taeg Chung
{"title":"CO-PERK-IRG1轴减轻肝缺血再灌注损伤中的氧化应激和铁下垂","authors":"Jeongmin Park , Min Zheng , Jeong Heon Gong , LiHua Jin , Stefan W. Ryter , Yeonsoo Joe , Hun Taeg Chung","doi":"10.1016/j.freeradbiomed.2025.08.042","DOIUrl":null,"url":null,"abstract":"<div><div>Hepatic ischemia-reperfusion injury (IRI) can arise as the consequence of surgical procedures, including liver transplant. Hepatic IRI is characterized by oxidative stress, inflammation, and activation of multiple regulated cell death pathways (RCD). Among RCD, ferroptosis is driven by enhanced lipid peroxidation and reactive oxygen species (ROS) formation. Carbon monoxide (CO), which can exert cytoprotective and anti-inflammatory properties, can mitigate IRI in various pre-clinical models when applied at low concentration, though the underlying mechanisms remain poorly understood. In this study, we describe a critical role of protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling in the protective effects of CO against oxidative stress and ferroptosis. We demonstrate that CO-induced PERK activation phosphorylates Nrf2, a master regulator of the cellular antioxidant response, leading to upregulation of immune-responsive gene 1 (IRG1) expression in both Kupffer cells (KCs) and hepatocytes. IRG1-derived itaconate production suppressed ROS accumulation and ferroptosis by enhancing GPX4 levels, while reducing ACSL4 and PTGS2 expression. Genetic interference of PERK or Nrf2 using siRNA or knockout mice abolished CO-mediated IRG1 induction and protection against ferroptosis, highlighting the indispensable role of this pathway.</div><div>Furthermore, in an <em>in vivo</em> model of hepatic IRI, CO treatment significantly reduced inflammation, histopathological damage, and ferroptosis in a manner dependent on the PERK-Nrf2-IRG1 axis. These findings establish the PERK-Nrf2-IRG1-itaconate pathway as a novel therapeutic target for hepatic IRI and potentially other ferroptosis-driven conditions.</div></div>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"240 ","pages":"Pages 253-266"},"PeriodicalIF":8.2000,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"CO-PERK-IRG1 axis attenuates oxidative stress and ferroptosis in hepatic ischemia-reperfusion injury\",\"authors\":\"Jeongmin Park , Min Zheng , Jeong Heon Gong , LiHua Jin , Stefan W. Ryter , Yeonsoo Joe , Hun Taeg Chung\",\"doi\":\"10.1016/j.freeradbiomed.2025.08.042\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Hepatic ischemia-reperfusion injury (IRI) can arise as the consequence of surgical procedures, including liver transplant. Hepatic IRI is characterized by oxidative stress, inflammation, and activation of multiple regulated cell death pathways (RCD). Among RCD, ferroptosis is driven by enhanced lipid peroxidation and reactive oxygen species (ROS) formation. Carbon monoxide (CO), which can exert cytoprotective and anti-inflammatory properties, can mitigate IRI in various pre-clinical models when applied at low concentration, though the underlying mechanisms remain poorly understood. In this study, we describe a critical role of protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling in the protective effects of CO against oxidative stress and ferroptosis. We demonstrate that CO-induced PERK activation phosphorylates Nrf2, a master regulator of the cellular antioxidant response, leading to upregulation of immune-responsive gene 1 (IRG1) expression in both Kupffer cells (KCs) and hepatocytes. IRG1-derived itaconate production suppressed ROS accumulation and ferroptosis by enhancing GPX4 levels, while reducing ACSL4 and PTGS2 expression. Genetic interference of PERK or Nrf2 using siRNA or knockout mice abolished CO-mediated IRG1 induction and protection against ferroptosis, highlighting the indispensable role of this pathway.</div><div>Furthermore, in an <em>in vivo</em> model of hepatic IRI, CO treatment significantly reduced inflammation, histopathological damage, and ferroptosis in a manner dependent on the PERK-Nrf2-IRG1 axis. These findings establish the PERK-Nrf2-IRG1-itaconate pathway as a novel therapeutic target for hepatic IRI and potentially other ferroptosis-driven conditions.</div></div>\",\"PeriodicalId\":12407,\"journal\":{\"name\":\"Free Radical Biology and Medicine\",\"volume\":\"240 \",\"pages\":\"Pages 253-266\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2025-08-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Free Radical Biology and Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0891584925009293\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Free Radical Biology and Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0891584925009293","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
CO-PERK-IRG1 axis attenuates oxidative stress and ferroptosis in hepatic ischemia-reperfusion injury
Hepatic ischemia-reperfusion injury (IRI) can arise as the consequence of surgical procedures, including liver transplant. Hepatic IRI is characterized by oxidative stress, inflammation, and activation of multiple regulated cell death pathways (RCD). Among RCD, ferroptosis is driven by enhanced lipid peroxidation and reactive oxygen species (ROS) formation. Carbon monoxide (CO), which can exert cytoprotective and anti-inflammatory properties, can mitigate IRI in various pre-clinical models when applied at low concentration, though the underlying mechanisms remain poorly understood. In this study, we describe a critical role of protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling in the protective effects of CO against oxidative stress and ferroptosis. We demonstrate that CO-induced PERK activation phosphorylates Nrf2, a master regulator of the cellular antioxidant response, leading to upregulation of immune-responsive gene 1 (IRG1) expression in both Kupffer cells (KCs) and hepatocytes. IRG1-derived itaconate production suppressed ROS accumulation and ferroptosis by enhancing GPX4 levels, while reducing ACSL4 and PTGS2 expression. Genetic interference of PERK or Nrf2 using siRNA or knockout mice abolished CO-mediated IRG1 induction and protection against ferroptosis, highlighting the indispensable role of this pathway.
Furthermore, in an in vivo model of hepatic IRI, CO treatment significantly reduced inflammation, histopathological damage, and ferroptosis in a manner dependent on the PERK-Nrf2-IRG1 axis. These findings establish the PERK-Nrf2-IRG1-itaconate pathway as a novel therapeutic target for hepatic IRI and potentially other ferroptosis-driven conditions.
期刊介绍:
Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.