tetano
Editor, Senior Moderator
Redox Biol
. 2025 Feb 26:81:103572.
doi: 10.1016/j.redox.2025.103572. Online ahead of print. Indoleamine 2,3-dioxygenase 1 drives epithelial cells ferroptosis in influenza-induced acute lung injury
Yongxin Zheng[SUP] 1 [/SUP], Yu Zhang[SUP] 2 [/SUP], Yubiao Chen[SUP] 1 [/SUP], Xiumei Deng[SUP] 1 [/SUP], Baiyun Liu[SUP] 1 [/SUP], Qiang Xu[SUP] 3 [/SUP], Chuyun Qian[SUP] 4 [/SUP], Zhihui Zhang[SUP] 1 [/SUP], Ke Wang[SUP] 1 [/SUP], Yuan Zeng[SUP] 1 [/SUP], Zhenting Liang[SUP] 1 [/SUP], Ling Sang[SUP] 1 [/SUP], Lingbo Nong[SUP] 1 [/SUP], Xiaoqing Liu[SUP] 1 [/SUP], Yonghao Xu[SUP] 1 [/SUP], Yimin Li[SUP] 5 [/SUP], Yongbo Huang[SUP] 6 [/SUP]
Affiliations
Acute lung injury (ALI) is a life-threatening complication of influenza A virus (IAV) infection, characterized by high morbidity and mortality. Recent studies have implicated ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, in the pathogenesis of IAV-induced ALI. However, the underlying mechanisms and key regulators of IAV-induced ferroptosis remain largely unknown. In this study, we found that IAV infection induces predominant ferroptosis in alveolar and bronchial epithelial cells, contributing to tissue damage and the development of acute lung injury. Treatment with the ferroptosis inhibitor ferrostatin-1 improved survival, mitigated weight loss, and alleviated lung injury in IAV-infected mice. Mechanistically, IAV-induced ferroptosis was associated with excess lipid peroxidation, nitrative stress, and disrupted iron metabolism. Targeted lipidomic analysis revealed that phospholipid peroxidation is a crucial mechanism in IAV-induced ferroptosis. Importantly, we identified indoleamine 2,3-dioxygenase 1 (IDO1) as a key regulator of IAV-induced ferroptosis. IDO1 knockdown inhibited IAV-induced cell death, and reduced intracellular reactive oxygen species, peroxynitrite, and inducible nitric oxide synthase expression. Furthermore, pharmacological inhibition of IDO1 with 1-methyl-tryptophan improved ALI phenotype in IAV-infected mice. These findings highlight the critical role of ferroptosis in IAV-induced ALI pathogenesis and identify IDO1 as a potential therapeutic target for the treatment of this life-threatening condition.
Keywords: Acute lung injury; Acute respiratory distress syndrome; Indoleamine 2,3-dioxygenase 1; Influenza a virus; Iron accumulation; Nitrative stress; Oxidative stress.
. 2025 Feb 26:81:103572.
doi: 10.1016/j.redox.2025.103572. Online ahead of print. Indoleamine 2,3-dioxygenase 1 drives epithelial cells ferroptosis in influenza-induced acute lung injury
Yongxin Zheng[SUP] 1 [/SUP], Yu Zhang[SUP] 2 [/SUP], Yubiao Chen[SUP] 1 [/SUP], Xiumei Deng[SUP] 1 [/SUP], Baiyun Liu[SUP] 1 [/SUP], Qiang Xu[SUP] 3 [/SUP], Chuyun Qian[SUP] 4 [/SUP], Zhihui Zhang[SUP] 1 [/SUP], Ke Wang[SUP] 1 [/SUP], Yuan Zeng[SUP] 1 [/SUP], Zhenting Liang[SUP] 1 [/SUP], Ling Sang[SUP] 1 [/SUP], Lingbo Nong[SUP] 1 [/SUP], Xiaoqing Liu[SUP] 1 [/SUP], Yonghao Xu[SUP] 1 [/SUP], Yimin Li[SUP] 5 [/SUP], Yongbo Huang[SUP] 6 [/SUP]
Affiliations
- PMID: 40023977
- DOI: 10.1016/j.redox.2025.103572
Acute lung injury (ALI) is a life-threatening complication of influenza A virus (IAV) infection, characterized by high morbidity and mortality. Recent studies have implicated ferroptosis, a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, in the pathogenesis of IAV-induced ALI. However, the underlying mechanisms and key regulators of IAV-induced ferroptosis remain largely unknown. In this study, we found that IAV infection induces predominant ferroptosis in alveolar and bronchial epithelial cells, contributing to tissue damage and the development of acute lung injury. Treatment with the ferroptosis inhibitor ferrostatin-1 improved survival, mitigated weight loss, and alleviated lung injury in IAV-infected mice. Mechanistically, IAV-induced ferroptosis was associated with excess lipid peroxidation, nitrative stress, and disrupted iron metabolism. Targeted lipidomic analysis revealed that phospholipid peroxidation is a crucial mechanism in IAV-induced ferroptosis. Importantly, we identified indoleamine 2,3-dioxygenase 1 (IDO1) as a key regulator of IAV-induced ferroptosis. IDO1 knockdown inhibited IAV-induced cell death, and reduced intracellular reactive oxygen species, peroxynitrite, and inducible nitric oxide synthase expression. Furthermore, pharmacological inhibition of IDO1 with 1-methyl-tryptophan improved ALI phenotype in IAV-infected mice. These findings highlight the critical role of ferroptosis in IAV-induced ALI pathogenesis and identify IDO1 as a potential therapeutic target for the treatment of this life-threatening condition.
Keywords: Acute lung injury; Acute respiratory distress syndrome; Indoleamine 2,3-dioxygenase 1; Influenza a virus; Iron accumulation; Nitrative stress; Oxidative stress.