STEAP3 alleviates inflammation and fibrosis via iron metabolism in ischemia/reperfusion-associated lung injury
Year: 2025
Type: article
Abstract: Lower limb ischemia/reperfusion (LIRI)-associated lung injury is a common complication observed in patients with lower extremity occlusion and prolonged tourniquet exposure, leading to significant morbidity and mortality. The lung is the primary remote organ affected by LIRI, owing to its high oxygen demands. Excessive iron accumulation has been implicated in pulmonary injury pathogenesis. Although STEAP3, a key regulator of iron metabolism, has been shown to play a role in various organ injuries and inflammation, but its involvement in LIRI-associated lung injury has not been explored. In this study, we investigated the role of STEAP3 in LIRI-induced lung injury using a mouse model of tourniquet-induced LIRI. Lung injury severity was assessed by wet/dry weight ratio, pro-inflammatory cytokines (IL-1β, IL-6), and the pro-fibrotic marker TGF-β1. Bulk RNA sequencing of lung tissues identified differentially expressed genes and pathways. In vitro, a hypoxia/re‑oxygenation (H/R) model and iron treatment were employed using HUVEC cells. The results showed significant lung edema, macrophage infiltration, and elevated inflammation in LIRI mice, accompanied by iron overload in endothelial cells. Pathway analysis revealed that differentially expressed genes were enriched in inflammatory response regulation and ferroptosis. Both in vivo and in vitro models exhibited activation of the NF-κB and TGFβ1/SMAD pathways, with STEAP3 expression reduced in LIRI and H/R conditions. Overexpression of STEAP3 reversed iron accumulation and inhibited NF-κB and TGFβ1/SMAD signaling. These findings suggest that excessive iron accumulation exacerbates LIRI-associated lung injury, and STEAP3 acts as a potential therapeutic target, offering protection by modulating inflammatory and fibrotic signaling pathways.
Authors: Wang Shaohui, Kong Xiangzhen, Yang Jingyi, Tong Jindong, Tian Ye, Lin Xueguang, Chen Bo, Lu Yijie, Wang Jiucun, Ling Xinyu, Tang Jingdong, Jiang Shuai
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,010
Funders: Shanghai Municipal Health Commission, National Natural Science Foundation of China, Fudan University, Health and Family Planning Committee of Pudong New Area, Science and Technology Department of Xinjiang Uyghur Autonomous Region, Shanghai Pudong New Area Health Commission, Shanghai Key Discipline Construction Project
OpenAlex ID: W4410596161