Iron metabolism dysregulation and ferroptosis: Emerging drivers in pulmonary fibrosis pathogenesis and therapy

Abstract

Ferroptosis is an iron-dependent and regulated form of cell death, characterized by lipid peroxidation and oxidative stress. The progressive development of pulmonary fibrosis (PF) is closely linked to the ferroptosis pathway. Although the underlying mechanisms remain incompletely defined, this field has drawn intense research attention. Notable progress has been made in identifying ferroptosis-related metabolic pathways and key targets during PF development. In this review, we first summarize the basic regulation of iron metabolism in the human lung, iron metabolic imbalance, and the activation of ferroptosis. Second, we focus on elaborating the mechanistic connections between ferroptosis and PF, encompassing the clinical features, pathological manifestations, and core pathogenic mechanisms of PF, as well as the interplay between ferroptosis and 3 specific cell types in PF: alveolar epithelial cells, macrophages, and fibroblasts. Third, the research progress in the pharmacotherapy of PF is categorized into 3 categories: drugs already approved for PF and those under clinical trials; ferroptosis-targeted therapeutic strategies, including inhibitors, natural compounds, gene therapy, and combination strategies. This review, grounded in key metabolic pathways and therapeutic targets, systematically explores the complex relationships among iron metabolic disorders, ferroptosis, and PF progression. Our aim is to provide a theoretical and practical foundation for ferroptosis-targeted PF treatment.