Iron Dysregulation and Ferroptosis as Novel Targets in Pulmonary Fibrosis

Iron metabolism imbalance and ferroptosis—a regulated, iron-dependent form of cell death—are emerging as central drivers in the development of pulmonary fibrosis (PF). A recent review published in Molecules and Cells underscores how targeting these pathways could unlock new therapeutic strategies for a disease with few effective treatments and a grim prognosis.¹

Despite advances, median survival for patients with PF remains just 3 to 5 years after diagnosis. Currently approved drugs pirfenidone (Esbriet; Genentech) and nintedanib (Ofev; Boehringer Ingelheim) slow disease progression but cannot halt or reverse fibrosis, and lung transplantation remains the only definitive therapy for advanced cases.

The researchers emphasized that ferroptosis affects different lung cells in distinct but interconnected ways that may drive pulmonary fibrosis. | Image credit: mi_viri - stock.adobe.com

Against this backdrop, researchers are increasingly turning to ferroptosis as a mechanistic link between oxidative stress, iron overload, and fibrotic remodeling in the lungs. Previous research has characterized the role of ferroptosis in the progression of PF, resulting in macrophage polarization, proliferation of fibroblasts, and ECM deposition, and eventually contributing to alveolar cell death and scarring of the lung tissue.²

Ferroptosis is a type of programmed cell death triggered by iron-dependent lipid peroxidation. Unlike apoptosis, it is characterized by oxidative damage to cell membranes, driven by excess ferrous iron (Fe²⁺) and reactive oxygen species (ROS). In the lung, iron accumulation disrupts homeostasis, triggering ferroptosis in key cell types—alveolar epithelial cells (AECs), macrophages, and fibroblasts—that together orchestrate fibrosis.

Animal models have shown that iron chelators and ferroptosis inhibitors can mitigate fibrosis by preserving epithelial integrity, suppressing macrophage-driven inflammation, and limiting fibroblast activation. These findings highlight ferroptosis as a potential “regulatory hub” in PF pathogenesis.

The authors explained that ferroptosis is not unique to PF but represents a conserved mechanism across fibrotic diseases of the lung, liver, and kidney.¹ This suggests that therapies developed for PF could have cross-organ benefits.

In the new review, the researchers emphasized that ferroptosis affects different lung cells in distinct but interconnected ways:

• AECs: Chronic injury and iron overload weaken epithelial repair capacity. Ferroptosis of AECs promotes abnormal wound healing and fibrogenesis. Inhibitors such as deferoxamine (an iron chelator) and liproxstatin-1 have been shown in preclinical models to protect AECs and reduce fibrosis progression
• Alveolar macrophages (AMs): Iron-laden macrophages accumulate in fibrotic lungs, releasing profibrotic cytokines like TGF-β. Their ferroptosis amplifies oxidative stress and fibroblast activation. Reducing transferrin receptor (TfR1) expression on AMs with iron chelators alleviates fibrosis in mouse models
• Alveolar fibroblasts (AFs): As terminal effectors of scarring, fibroblasts differentiate into collagen-secreting myofibroblasts. Ferroptosis modulates this transition, with excess iron driving collagen cross-linking and scar formation. Targeting ferroptotic pathways in AFs could blunt extracellular matrix deposition

This “triad” of ferroptosis across AECs, AMs, and AFs forms the cellular foundation of progressive PF, explained the researchers.

The group noted that ferroptosis-related biomarkers could aid earlier diagnosis and personalized treatment. Elevated lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), high serum ferritin, and reduced glutathione peroxidase 4 (GPX4) activity in lung tissue are hallmarks of ferroptosis in PF.

These biomarkers not only distinguish PF from other lung conditions but also track disease progression and treatment response. For example, liproxstatin-1 has been shown to reduce MDA levels and restore GPX4 activity in experimental PF, correlating with improved lung function.

At the preclinical level, ferroptosis-targeted drugs such as liproxstatin-1 and natural compounds like triptolide are showing promise, though the researchers note that, “Despite the promising preclinical results, the clinical translation of ferroptosis inhibitors (e.g., liproxstatin-1) still faces key challenges: poor in vivo metabolic stability and rapid clearance; lack of lung-targeted delivery systems, which limits bioavailability at fibrotic lesion sites; and crosstalk with other cell death pathways (such as the ROS-TGF-β axis), which may trigger off-target effects.”

Gene therapy strategies and combination approaches, such as pairing ferroptosis inhibitors with traditional antifibrotics, are also being explored in addition to the PDE4B inhibitor nerandomilast, the recombinant pentraxin-2 analog PRM-151, and the antibody pamrevlumab.

References

1. Jiang Y, Zhang L, Lin Y, et al. Iron metabolism dysregulation and ferroptosis: emerging drivers in pulmonary fibrosis pathogenesis and therapy. Mol Cells. Published online August 6, 2025. doi:10.1016/j.mocell.2025.100264

2. Hu Y, Huang Y, Zong L, Lin J, Liu X, Ning S. Emerging roles of ferroptosis in pulmonary fibrosis: current perspectives, opportunities and challenges. Cell Death Discov. 2024;10(1):301. doi:10.1038/s41420-024-02078-0