REVIEW article
Front. Immunol.
Sec. Molecular Innate Immunity
Ferroptosis-Immune-Metabolic Axis in Asthma: Mechanistic Crosstalk, Endotype-Specific Regulation, and Translational Targeting
Provisionally accepted
- Affiliated Zhuhai Hospital, Southern Medical University, Zhuhai Hospital of Integrated Traditional Chinese & Western Medicine, Zhuhai 519000, Guangdong, China., Zhuhai, China
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Asthma, a heterogeneous chronic respiratory disorder affecting millions globally, is driven by complex interactions between genetic susceptibility, environmental triggers, and dysregulated immunity. Emerging evidence positions ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, as a pivotal mechanism. This review introduces the "Ferroptosis-Immune-Metabolic Axis" as an integrative framework for asthma pathogenesis. We detail how environmental insults (e.g., allergens, pollutants) initiate ferroptosis in airway epithelial cells, leading to the release of damage-associated molecular patterns (DAMPs) and lipid peroxidation products (e.g., 4-HNE). These molecules activate and recruit immune cells (M1 macrophages, neutrophils, Th17 cells), which in turn exacerbate oxidative stress and iron dysregulation, creating a self-amplifying cycle. Metabolic reprogramming, including enhanced polyunsaturated fatty acid (PUFA) synthesis and glycolytic flux, provides the essential substrates and energy to sustain this vicious cycle. We dissect endotype-specific manifestations: IL-33-driven epithelial ferroptosis in eosinophilic asthma and ALOX15-mediated lipid peroxidation coupled with hepcidin-induced iron retention in neutrophilic asthma. Therapeutically, we highlight novel strategies such as inhaled GPX4 mRNA nanocarriers and ALOX15 inhibitors, underscoring the potential of targeting this axis for precision medicine in refractory asthma.
Keywords: ferroptosis, Asthma, Ferroptosis-immune-metabolic axis, airway inflammation, Endotype-specific therapy, precision medicine
Received: 14 Oct 2025; Accepted: 08 Dec 2025.
Copyright: © 2025 Ni, Hu, Chen, Chen, Huang and Jiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zebo Jiang
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