Targeting the MALT1–MIF–IL-21/IL-17 axis restores glucocorticoid sensitivity in infection-associated steroid-resistant asthma

Steroid-resistant asthma (SRA) driven by airway infection and neutrophilic inflam-mation remains poorly treatable with glucocorticoids (GCs). Using a recombinant Pseudomonas aeruginosa exotoxin A (rPEA)-induced mouse model, we reveal MALT1 as an upstream regulator of GC resistance. rPEA triggered neutrophilic in-flammation, hyperresponsiveness, and remodeling unresponsive to GCs, alongside suppressed glucocorticoid receptor (GR) and histone deacetylase 2 (HDAC2) activity. MALT1 activation induced macrophage migration inhibitory factor (MIF), which enhanced IL-21 and IL-17A–dependent inflammation. Disrupting IL-21/IL-21R or IL-17A signaling partially restored GC sensitivity. Inhibiting MALT1 or MIF reduced inflammation and reactivated GR/HDAC2 signaling. Combining MALT1/MIF inhi-bition with dexamethasone synergistically ameliorated airway disease. Our results establish MALT1 as a key mediator of steroid resistance via the MIF–IL-21–IL-17 axis, offering a therapeutic strategy to restore GC responsiveness in infection-related SRA.