Mesothelial plasticity regulates lung mechanical homeostasis in regeneration and fibrosis.

Tissue mechanical adaptation is fundamental to organ development, regeneration, and disease, yet the cellular mechanisms that regulate tissue mechanical adaptation remain poorly understood. Here, we show that mesothelial cells are key regulators of lung mechanical adaptation. Following pneumonectomy, elevated stretch activates YAP (yes-associated protein 1) and induces a transient fibroblast-like mesothelial cell state (F-LMC) characterized by reduced mesothelial identity, increased fibroblast features, and extracellular matrix remodeling at the pleural surface. Yap deletion suppresses F-LMC formation, resulting in lung overinflation and defective regeneration following pneumonectomy. By contrast, in fibrotic lungs, this mesothelial remodeling program is aberrantly activated and restricts lung inflation. Inhibition of this maladaptive response prevents the decline in lung capacity following bleomycin-induced pulmonary fibrosis. Collectively, our findings redefine the mesothelium as a mechanosensitive regulator of organ-scale mechanical adaptation and reveal how pleural surface remodeling controls tissue mechanics during regeneration and disease.