MUC1 attenuates chronic obstructive pulmonary disease through integrated regulation of pulmonary epithelial cell senescence, transdifferentiation, and inflammatory cascades

Impaired pulmonary epithelial cell homeostasis is a key pathogenic feature in chronic obstructive pulmonary disease (COPD). Mucin 1 (MUC1/Muc1) is a membrane-tethered glycoprotein that plays important roles in modulating various disease progression. This study aims to decipher the role and mechanisms of MUC1 in the pathogenesis of COPD. We found functional variants (rs4072037 T > C and rs12411216 C > A) in MUC1 were associated with increased susceptibility to COPD. MUC1-C expression in lung tissues was age-dependent, elevated in adults but decreased in elderly COPD patients. Aged Muc1-deficient mice showed increased cellular senescence in alveolar type II (AT2) epithelial cells and spontaneously developed emphysema. In cigarette smoke (CS)-induced COPD model mice, Muc1 deficiency caused an accelerated decline in lung function, impaired mitochondrial function, enhanced lung inflammation, and impaired AT2-to- alveolar type I (AT1) epithelial cell transdifferentiation. Adeno-associated virus serotype 9 (AAV9)-mediated AT2 cell-specific reconstitution of Muc1 ameliorated COPD in association with integrated suppression of pulmonary inflammation and enhancement of AT2 transdifferentiation and mitochondrial function. Mechanistically, we found MUC1 attenuated senescence and associated cell dysfunction, including activation of PINK1/Parkin-dependent mitophagy flux and AMPK/NDUFS4-driven mitochondrial metabolic reprogramming in AT2 cells. In addition, MUC1 modulated CS extract (CSE)-induced human AT2-to-AT1 transdifferentiation through enhancement of β-catenin nuclear translocation. Moreover, overexpression of MUC1 in lung epithelial cells inhibited CS-induced NF-κB activation and inflammatory responses in both in vitro and in vivo. Collectively, this study identified MUC1 as a protective molecule and potential target for COPD, particularly emphysema, via facilitating AT2-to-AT1 cell transdifferentiation, while prohibiting senescence and inflammation.