BMAL1 deficiency exacerbates HDM-induced asthma by promoting JUN-mediated lipid peroxidation and airway epithelial ferroptosis.

Asthma exhibits pronounced circadian variation, yet the molecular mechanisms linking clock disruption to airway epithelial injury remain unclear. In this study, we identify the core clock component BMAL1 as a critical epithelial regulator that restrains ferroptosis-associated injury during allergic airway inflammation. Using a house dust mite (HDM)-induced murine asthma model and HDM-stimulated human bronchial epithelial cells, we found that BMAL1 expression was significantly reduced, whereas BMAL1 deficiency markedly aggravated airway inflammation, mucus metaplasia, and remodeling. Integrated transcriptomic and metabolomic analyses revealed a signature of inflammatory activation and metabolic reprogramming linked to ferroptosis. Consistently, BMAL1 deficiency increased lipid peroxidation and reactive oxygen species levels, downregulated GPX4 and xCT (SLC7A11), and upregulated COX2 expression in the airway epithelium both in vivo and in vitro. Treatment with Ferrostatin-1 attenuated these alterations and partially rescued the aggravated asthmatic phenotype in Bmal1-deficient mice. Notably, constitutive overexpression of BMAL1 also worsened HDM-induced airway pathology, suggesting that disruption of BMAL1 rhythmic oscillation contributes to disease progression. Mechanistically, BMAL1 deficiency activated the AP-1 pathway, induced COX2 expression, and promoted ferroptosis-associated epithelial injury, whereas inhibition of JUN alleviated this phenotype. Furthermore, melatonin also mitigated the aggravated airway pathology and ferroptosis-related changes associated with BMAL1 deficiency. Collectively, these findings identify BMAL1 as a key regulator of airway epithelial ferroptosis and highlight JUN signaling, together with COX2-associated prostaglandin responses, as downstream components of asthma exacerbations driven by circadian dysregulation.