Potential Role of Ferroptosis in Sterile Acute Lung Injury Induced by a Non-Hypoxic Ischemia-Reperfusion Insult Publisher



Kianian F ; Tian X ; Maruyama D ; Prakash A
Source: Iranian Journal of Basic Medical Sciences Published:2026

Abstract

Objective(s): Ferroptosis, a regulated form of necrotic cell death, is implicated in the pathogenesis of hypoxic lung ischemia-reperfusion injury (LIRI). However, its role in non-hypoxic LIRI, which occurs in common clinical conditions such as trauma and pulmonary embolism, remains unclear. Given that ferroptosis has been implicated in sterile inflammation and lipid peroxidation is a hallmark of this process, this study aimed to investigate the potential role of ferroptosis in inflammatory responses during non-hypoxic LIRI. Materials and Methods: Non-hypoxic LIRI was induced in C57BL/6 mice by occluding the left pulmonary artery for 1 hr, followed by 30 min of reperfusion. The treatment group received liproxstatin-1 (Lip-1; 10 mg/kg, IP) 1 hr before surgery. IL-6 levels in plasma and lung tissue were measured by ELISA. For the in vitro model, normal human bronchial epithelial (NHBE) cells were exposed to nutritional ischemia for 1 hr and then reperfused for 2 hr. Cells were pretreated with Lip-1 (200 nM) 12 hr before ischemia. CXCL1 release was measured by ELISA, and lipid reactive oxygen species (ROS) accumulation was assessed by BODIPY 581/591 C11 fluorescence. Results: Non-hypoxic LIRI markedly increased IL-6 levels in plasma and lung tissue, as well as CXCL1 levels and lipid ROS accumulation in NHBE cells. Pretreatment with Lip-1 significantly reduced these inflammatory responses and lipid ROS accumulation compared with untreated LIRI. Conclusion: Our findings suggest that ferroptosis-associated lipid peroxidation is associated with sterile inflammatory responses during non-hypoxic LIRI in both systemic and epithelial compartments. Lip-1 attenuated these responses, highlighting a potential strategy for non-hypoxic LIRI. © 2026. This work is openly licensed via CC BY 4.0. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.