IRF1 rs2057656 Polymorphism Regulates IRF1-AS1 Transcription and Immune Dysfunction in ARDS via Allele-Specific Epigenetic Repression

Acute respiratory distress syndrome (ARDS) is a severe and life-threatening variant of respiratory failure. Effective targeted therapies are lacking, and patient heterogeneity is substantial. Interferon regulatory factor 1, a key inflammatory transcription factor implicated in ARDS pathogenesis, has poorly defined genetic regulation. By integrating clinical cohorts with genome-wide association studies, we identified a functional single-nucleotide polymorphism, rs2057656, in the antisense promoter of IRF1. The C allele significantly increased ARDS risk (odds ratio = 3.39). This variant modulates local DNA methylation, thereby regulating the expression of the antisense transcript IRF1-AS1, mediating histone deacetylation at the IRF1 promoter and establishing an epigenetic cascade, DNA methylation, antisense RNA, and histone modification that controls IRF1 transcription and pulmonary inflammation. Exogenous IRF1-AS1 delivery alleviated ARDS in C-allele mice. Our study systematically elucidates an epigenetic mechanism governing IRF1 expression and ARDS susceptibility, identifying a genotype-informed therapeutic target.