Chinese researchers have revealed the key role of iron in initiating allergic airway inflammation.
The study, which was published in Cell, was conducted by a team led by Prof. SUN Bing from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences (CAS), along with Prof. LIU Xing’s team from the Shanghai Institute of Materia and Medica of CAS.
The research showed that “environmental allergens can use an iron-dependent mechanism to activate gasdermin D (GSDMD)” in airway epithelial cells, thereby promoting IL-33 release and initiating allergic airway inflammation.
When environmental allergens such as pollen, house dust mites, and fungal proteases enter the airway, they act on lung epithelial cells and induce the release of alarmins, including IL-33. IL-33 then activates type 2 innate lymphoid cells (ILC2s), leading to eosinophil infiltration, mucus production, and airway tissue damage.
Previous studies have shown that GSDMD is involved in IL-33 release, but how allergens activate GSDMD had remained unclear. In this study, researchers found that allergen stimulation rapidly increased the labile iron pool in airway epithelial cells, and GSDMD was cleaved and activated through a mechanism independent of conventional proteases.
Using mouse models induced by papain or house dust mites, researchers observed a rapid rise in lung iron levels after allergen challenge. Treatment with an iron chelator markedly inhibited GSDMD cleavage and IL-33 release, whereas iron supplementation enhanced these responses. This effect was largely abolished in GSDMD-deficient mice.
The researchers showed that “cell-surface protease-activated receptor PAR1 serves as an important entry point for allergen sensing.” Papain directly cleaves PAR1, which initiates NCOA4-mediated ferritinophagy and releases additional free iron. The iron chaperone PCBP2 delivers iron to GSDMD, where specific residues are responsible for iron binding.
The cleavage process does not depend on canonical inflammasome-associated caspases. Instead, iron delivered by PCBP2 locally triggers a Fenton reaction, generating hydroxyl radicals that drive oxidative cleavage of GSDMD.
In vivo experiments showed that pretreatment with the iron chelator DFP significantly alleviates papain-induced airway inflammation, reducing eosinophil infiltration, IL-5 and IL-13 levels, and mucus secretion. Conversely, iron supplementation aggravated inflammatory responses in wild-type mice, but failed to produce the same effect in GSDMD-deficient mice.
These findings establish “the iron–GSDMD–IL-33 axis as an important driver of allergen-induced type 2 immune responses,” and suggest that PAR1, iron mobilization, PCBP2, and local iron-mediated reactions may represent potential intervention points for asthma and other allergic diseases.
Journal: Cell
DOI: 10.1016/j.cell.2026.06.004
Article Title: Iron drives protease-independent cleavage of gasdermin D in allergic airway diseases
Article Publication Date: 26-Jun-2026
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Source: EurekAlert