Iron drives protease-independent cleavage of gasdermin D in allergic airway diseases.

Iron-dependent, protease-independent activation of gasdermin D drives IL-33 release and airway inflammation in allergic diseases, with a key role for ferritinophagy and iron chaperones.

• Why it matters: Understanding how environmental allergens activate gasdermin D is crucial for developing targeted therapies for allergic airway diseases, as current mechanisms remain unclear.
• What they did: The study used cellular and mouse models to show that allergen exposure induces ferritinophagy and increases intracellular iron, which is delivered by PCBP2 to GSDMD, leading to its cleavage via a Fenton reaction.
• The result: Blocking this iron-GSDMD pathway prevents IL-33 secretion, reduces immune cell activation, and alleviates airway inflammation, highlighting a novel therapeutic target for allergic conditions.