SMAD4-BPIFA1 Axis Governs Airway Antiviral Defense in Myhre Syndrome.

Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function (GOF) variants in SMAD4. Although it is primarily recognized as a fibrotic disease, we and others have identified respiratory infection-associated morbidity as a major clinical burden. Regardless, the epithelial-intrinsic mechanisms underlying increased viral susceptibility in Myhre syndrome remain poorly understood. Here, using patient-derived nasal airway epithelial cells (NECs) and respiratory syncytial virus (RSV) infection as a model, we demonstrate that infection is markedly exacerbated in Myhre syndrome epithelium relative to matched healthy controls. We further show that activation of TGF-β1-SMAD4 signaling in healthy donor NECs phenocopies augmented RSV susceptibility, identifying SMAD4 signaling as a bona fide pro-viral pathway in airway epithelium. Mechanistically, we identify a significant reduction in BPIFA1 expression in Myhre syndrome NECs. BPIFA1 is a key secreted innate defense protein with antimicrobial, immunomodulatory, and emerging antiviral functions. SMAD signaling suppresses BPIFA1 expression, and its knockdown in healthy cells mimics the increased viral susceptibility, linking SMAD4 gain-of-function to impaired epithelial immunity. Therapeutically, we evaluated novel, stabilized 24-amino acid BPIFA1-derived peptides as a potential intervention. Treatment with active peptides (A4-153 and A4-X7) significantly reduced RSV infectivity and epithelial damage in both healthy and Myhre syndrome airway epithelial cultures, whereas a scrambled control peptide (A4-198) showed no significant effect. Collectively, our findings establish that GOF SMAD4 signaling enhances viral vulnerability in airway epithelium through suppression of BPIFA1-mediated antiviral defense and demonstrate that BPIFA1-derived peptide therapeutics represent a promising strategy to restore innate antiviral protection.