铁死亡与慢性肺部疾病的研究进展

Advances in the Study of Ferroptosis and Chronic Pulmonary Diseases

摘要: 慢性肺部疾病包括慢性阻塞性肺疾病、支气管哮喘、肺纤维化和肺动脉高压等，具有病程迁延、炎症持续、氧化应激增强和组织结构重塑等共同特征。铁死亡是一种由铁依赖性脂质过氧化驱动的调节性细胞死亡方式，其发生涉及铁稳态紊乱、胱氨酸/谷氨酸反向转运体/谷胱甘肽/谷胱甘肽过氧化物酶4轴受损、多不饱和脂肪酸磷脂氧化、线粒体功能异常及抗氧化防御失衡。肺组织长期处于高氧环境，并反复暴露于香烟烟雾、颗粒物、病原体和炎症介质，使气道上皮细胞、肺泡上皮细胞、巨噬细胞、成纤维细胞和肺血管细胞对铁死亡具有较高敏感性。现有研究表明，铁死亡可参与慢性阻塞性肺疾病中的上皮损伤和肺气肿形成、肺纤维化中的异常修复和胶原沉积、哮喘中的上皮屏障破坏及肺动脉高压中的血管重构。铁死亡相关指标有望用于疾病分层和疗效预测，靶向铁代谢、脂质过氧化和抗氧化通路也可能成为新的干预策略。然而，目前研究仍存在判定标准不统一、细胞特异性机制不足和临床转化证据有限等问题。未来应结合标准化检测、单细胞组学、空间组学和纵向临床队列，明确铁死亡在慢性肺部疾病中的时空特异性作用及治疗价值。

Abstract: Chronic pulmonary diseases, including chronic obstructive pulmonary disease, asthma, pulmonary fibrosis, and pulmonary hypertension, are characterized by persistent inflammation, oxidative stress, epithelial barrier injury, and progressive tissue remodeling. Ferroptosis is a regulated cell death program driven by iron-dependent lipid peroxidation and governed by iron dyshomeostasis, disruption of the System Xc⁻/glutathione/glutathione peroxidase 4 axis, oxidation of polyunsaturated fatty acid-containing phospholipids, mitochondrial dysfunction, and impaired antioxidant defense. The lung is particularly vulnerable to ferroptosis because it is continuously exposed to high oxygen tension, cigarette smoke, particulate matter, pathogens, and inflammatory mediators. These insults may sensitize airway epithelial cells, alveolar epithelial cells, macrophages, fibroblasts, and pulmonary vascular cells to ferroptotic damage. Emerging evidence links ferroptosis to epithelial injury and emphysema in chronic obstructive pulmonary disease, aberrant epithelial repair and collagen deposition in pulmonary fibrosis, epithelial barrier dysfunction in asthma, and vascular remodeling in pulmonary hypertension. Ferroptosis-related biomarkers may improve disease stratification and prediction of therapeutic response, while interventions targeting iron handling, lipid peroxidation, or antioxidant pathways may offer new treatment strategies. Nevertheless, the field is constrained by inconsistent diagnostic criteria, limited cell type-specific mechanistic data, and insufficient clinical validation. Future studies should combine standardized ferroptosis assays with single-cell and spatial omics and longitudinal patient cohorts to define the spatiotemporal functions and translational potential of ferroptosis in chronic pulmonary diseases.