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A significant proportion of patients exhibit inadequate responses to standard biological therapies targeting classical T helper Type 2 (Th2) inflammation. Current respiratory research is undergoing a fundamental conceptual transformation, expanding beyond isolated immune cell networks to investigate complex metabolic reprogramming and programmed cell death. This comprehensive review aims to elucidate the emerging role of iron homeostasis imbalance as a critical driver of airway pathology and its specific interaction with atypical structural protein cleavage. While traditional models identify Gasdermin D (GSDMD) as a terminal executioner activated by inflammatory proteases (caspases) in canonical pyroptosis, recent breakthroughs reveal a novel, protease\u2010independent GSDMD cleavage mechanism driven directly by iron overload and severe oxidative stress. This atypical iron\u2010GSDMD axis acts as a crucial intersection node between ferroptosis\u2010like lipid peroxidation and classical pyroptosis. The resulting GSDMD pore formation causes massive physical epithelial barrier destruction and the externalization of danger\u2010associated molecular patterns (DAMPs), IL\u20101\u03b2, and IL\u201018. This process exponentially amplifies local tissue inflammation, driving both classical Type 2 responses and atypical neutrophilic inflammation, ultimately leading to chronic, irreversible airway remodeling. The novel iron\u2010GSDMD axis fundamentally transforms our understanding of respiratory immunology and offers a compelling mechanistic explanation for refractory clinical presentations. Developing therapeutic interventions that incorporate active immune regulation, metabolic correction via iron modulation, and barrier restoration provides a transformative clinical paradigm for treating severe and treatment\u2010resistant allergic airway diseases.<\/jats:p>","DOI":"10.1096\/fj.202604032r","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:59:40Z","timestamp":1791820780000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gasdermin D Activation by Iron Overload Amplifies Allergic Airway Inflammation"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2817-0780","authenticated-orcid":false,"given":"Tianwei","family":"Pei","sequence":"first","affiliation":[{"name":"Department of Anesthesiology Dalian No. 3 People's Hospital  Dalian Liaoning Province 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