Yao Mingjun, Liu Zheng, Zhao Wei, Song Siyuan, Huang Xiaobo, Wang Yi
School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Pathology Department, University of Texas, MD Anderson Cancer Center, Houston, TX, United States.
Front Immunol. 2025 May 21;16:1567994. doi: 10.3389/fimmu.2025.1567994. eCollection 2025.
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring, alveolar destruction, and limited therapeutic options. Although the exact etiology of IPF remains unclear, emerging evidence suggests that ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative stress, plays a significant role in its pathogenesis. Ferroptotic stress not only compromises alveolar epithelial cell integrity, but also triggers inflammatory responses and profibrotic signaling cascades that activate and sustain fibroblast dysfunction. This review delineates the core regulatory pathways of ferroptosis, iron metabolism, lipid peroxidation, antioxidant defenses, mitochondrial remodeling, and RNA editing, with an emphasis on their relevance in IPF. We explore how epithelial injury and macrophage-derived signals initiate ferroptosis, and how fibroblast subsets, shaped by scRNA-seq-defined heterogeneity and plasticity, respond to these cues by reinforcing ECM deposition and oxidative stress. Therapeutic avenues targeting ferroptosis, including antioxidant supplementation, iron chelation, and modulation of lipid metabolism, are discussed alongside cell-specific interventions and nanodelivery strategies. By integrating recent advances in molecular profiling and ferroptosis biology, this review provides a framework for leveraging ferroptosis as a tractable target in IPF and identifies novel directions for precision antifibrotic therapy.
特发性肺纤维化（IPF）是一种致命的间质性肺疾病，其特征为进行性瘢痕形成、肺泡破坏且治疗选择有限。尽管IPF的确切病因仍不清楚，但新出现的证据表明，铁死亡（一种由脂质过氧化和氧化应激驱动的铁依赖性调节性细胞死亡形式）在其发病机制中起重要作用。铁死亡应激不仅损害肺泡上皮细胞的完整性，还引发炎症反应和促纤维化信号级联反应，激活并维持成纤维细胞功能障碍。本综述阐述了铁死亡、铁代谢、脂质过氧化、抗氧化防御、线粒体重塑和RNA编辑的核心调控途径，重点关注它们在IPF中的相关性。我们探讨上皮损伤和巨噬细胞衍生信号如何引发铁死亡，以及由单细胞RNA测序定义的异质性和可塑性塑造的成纤维细胞亚群如何通过加强细胞外基质沉积和氧化应激来响应这些信号。本文还讨论了针对铁死亡的治疗途径，包括补充抗氧化剂、铁螯合和调节脂质代谢，以及细胞特异性干预措施和纳米递送策略。通过整合分子图谱和铁死亡生物学的最新进展，本综述为将铁死亡作为IPF中一个易于处理的靶点提供了框架，并确定了精准抗纤维化治疗的新方向。
