Pharmacological EZH2 inhibition attenuates post-transplant obliterative bronchiolitis by reprogramming macrophage...

Bronchiolitis obliterans (OB) remains the primary limitation to long-term survival in lung transplant recipients, with current therapeutic strategies showing suboptimal efficacy. Growing evidence implicates macrophage-mediated pathways as critical drivers of post-transplant OB pathogenesis. Our integrated bioinformatics approach identified the histone methyltransferase EZH2 (enhancer of zeste homolog 2) as a central regulatory node in OB progression. Using an orthotopic murine tracheal transplantation model, we found that pharmacological EZH2 inhibition significantly attenuated OB-associated luminal stenosis and fibrotic remodeling and mitigated rejection-related immune responses. Through macrophage depletion studies and molecular characterization, we established that EZH2 exerts its effects by modulating STAT1 (signal transducer and activator of transcription 1) transcription, thereby inducing epigenetic reprogramming of macrophage polarization. These results provide mechanistic insight and therapeutic rationale for targeting the EZH2-STAT1-macrophage axis in post-transplant OB management.