Upregulated CCN1 from pleural mesothelial cells alters collagen I conformation and drives fibrosis via ITGB1/MAPK signaling

Pleural mesothelial cells (PMCs) have been identified as key contributors to pleural fibrosis. Cellular communication network factor 1 (CCN1), a matricellular protein, regulates cell–matrix interactions and fibrotic signaling in multiple contexts. However, the specific role and mechanism of CCN1 in PMCs during pleural fibrosis remained unclear. Expression of CCN1 was evaluated in human pleural fibrosis samples and bleomycin-induced mouse models. In vitro, PMCs were treated with recombinant CCN1 or fibrotic matrix. Mechanistic studies included gene knockdown, immunoprecipitation, mass spectrometry, and functional assays. CCN1 was significantly elevated in pleural fibrosis tissues. CCN1 expression was driven by YAP/TAZ activation and in turn promoted further YAP/TAZ activation, creating a feedback loop to produce more CCN1. Upregulated CCN1 directly altered conformation of type I collagen (collagen I) by binding vWC binding domain. Then, CCN1 with conformation-changed collagen I activated integrin β1 (ITGB1)/MAPK signaling, which induced remodeling of cytoskeleton as well as fibrosis. At last, it was confirmed that neutralization of CCN1 reduced pleural fibrosis in vitro and in vivo. Upregulated CCN1 contributes to pleural fibrosis via changing collagen I conformation and ITGB1/MAPK pathway activation. Targeting CCN1 is a potential therapeutic strategy.