Ferroptosis in idiopathic pulmonary fibrosis: mechanisms, impact, and therapeutic opportunities

Abstract

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.

Keywords: ferroptosis; idiopathic pulmonary fibrosis (IPF); immune homeostasis; interleukin; toll-like receptor; transforming growth factor; tumor necrosis factor; type I interferon.

Figure 1

Integration of ferroptosis pathways with fibrogenic signaling in idiopathic pulmonary fibrosis (IPF). This schematic outlines the molecular crosstalk between ferroptosis and pro-fibrotic pathways in IPF. Iron uptake through transferrin receptor 1 (TfR1) and reduction by STEAP3 and DMT1 leads to intracellular Fe²⁺ accumulation, which catalyzes ROS production via the Fenton reaction. Oxidative lipid metabolism mediated by lipoxygenases and P450 oxidoreductase contributes to lipid peroxidation, a key step in ferroptosis. Glutathione (GSH) synthesis and GPX4 activity act as antioxidant defenses against lipid peroxides, while ACSL4 facilitates the incorporation of polyunsaturated fatty acids (PUFAs) into membrane phospholipids, increasing vulnerability to peroxidation. The figure also illustrates how ferroptosis intersects with the TGF-β/Smad and TLR4/NF-κB pathways—major drivers of fibrosis. TGF-β signaling activates Smad2/3/4 complexes, leading to transcriptional induction of fibrosis-associated genes. Concurrently, TLR4 signaling via MyD88 activates NF-κB, promoting the expression of pro-inflammatory cytokines. These pathways may be further amplified by ferroptotic cell death and ROS, exacerbating tissue damage and fibrotic remodeling. miR-155-5p and other regulators are implicated in enhancing ACSL4 expression, linking immune signaling to ferroptotic susceptibility. Together, this figure illustrates a feedforward loop between ferroptosis and fibrogenesis in IPF.