Ferroptosis Mechanisms in Pulmonary Pathologies

Ferroptosis is a regulated form of cell death driven by iron‐dependent lipid peroxidation and disruption of cellular redox homeostasis. In the lung, this pathway has been implicated in a spectrum of pathologies, from chronic obstructive pulmonary disease and asthma to acute respiratory distress syndrome, radiation-induced injury and fibrotic remodelling. Central to the process are dysregulated iron handling, depletion of antioxidant defences and accumulation of peroxidised phospholipids, which together compromise membrane integrity and mitochondrial function. Emerging work highlights the interplay between ferroptosis and organelle quality control mechanisms such as mitophagy, as well as cross-talk with inflammatory signalling axes. Recognition of these interconnected processes has spurred interest in targeting key nodes—such as glutathione peroxidase 4, the cystine/glutamate antiporter and lipid‐metabolising enzymes—to arrest disease progression and preserve pulmonary function.

Research from Nature Portfolio

Recent studies have revealed a compartmentalised form of mitochondrial lipid peroxidation in airway epithelial cells that does not culminate in immediate cell death but instead triggers PINK1–Parkin–Optineurin-mediated mitophagy. This finely tuned response preserves a functional mitochondrial pool, prevents overt epithelial loss and influences ciliated cell abundance in asthma models, suggesting that selective ferroptotic processes may be harnessed to restore epithelial integrity. Earlier work in chronic obstructive pulmonary disease has demonstrated that cigarette smoke prompts labile iron accumulation and enhanced phospholipid peroxidation in lung epithelium. This non-apoptotic death pathway is negatively regulated by glutathione peroxidase 4 activity and ferritinophagy via NCOA4, underscoring a causal link between environmental insult, iron homeostasis and ferroptosis in disease pathogenesis.

Ferroptosis Mechanisms in Pulmonary Pathologies publication trend

The graph below shows the total number of articles in ferroptosis mechanisms in pulmonary pathologies across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: A form of regulated cell death characterised by iron-dependent phospholipid peroxidation and loss of redox balance.

Lipid peroxidation: Oxidative degradation of polyunsaturated lipids in membranes, leading to cellular dysfunction.

Glutathione peroxidase 4 (GPX4): A selenoenzyme that reduces lipid hydroperoxides and counteracts ferroptosis.

SLC7A11 (System x_c^−): Cystine/glutamate antiporter that maintains intracellular glutathione levels and protects against ferroptosis.

Mitophagy: Selective autophagic removal of damaged mitochondria to maintain cellular health.

Exosomes: Small extracellular vesicles that mediate intercellular transfer of proteins, lipids and nucleic acids.

References

1. Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes. Nature Communications (2024).
2. Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. Nature Communications (2019).
3. Characterization of dipyridamole as a novel ferroptosis inhibitor and its therapeutic potential in acute respiratory distress syndrome management. Theranostics (2024).
4. Ficolin B secreted by alveolar macrophage exosomes exacerbates bleomycin-induced lung injury via ferroptosis through the cGAS-STING signaling pathway. Cell Death & Disease (2023).
5. Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury. Cell Death Discovery (2022).