Purpose <p>The pleural microenvironment has long been considered a passive anatomical boundary. However, emerging evidence identifies it as an active regulator of inflammation, tissue repair, and fibrotic remodeling. This review evaluates the mechanistic contribution of pleural mesothelial cells (PMCs) to pulmonary injury and fibrosis and explores their potential role in coordinating regenerative responses.</p> Methods <p> Recent preclinical and clinical studies investigating pleural biology, mesothelial plasticity, mesothelial-mesenchymal transition (MesoMT), and pulmonary fibrosis were critically analyzed. Evidence from cutaneous wound healing was integrated to identify common molecular pathways governing tissue repair and fibrotic progression</p> Results <p>PMCs actively participate in pulmonary remodeling by secreting cytokines, growth factors, and extracellular matrix regulators. Persistent activation of TGF-β/Smad, Wnt/β-catenin, PI3K/Akt, and IL-6/STAT3 signaling promotes MesoMT, myofibroblast accumulation, and progressive extracellular matrix deposition in pulmonary fibrosis. Conversely, pleural-derived mediators have demonstrated regenerative potential by enhancing epithelial proliferation, migration, angiogenesis, and tissue repair in experimental models. Collectively, current evidence suggests that pleural signaling functions as a context-dependent regulatory network that influences the transition between effective regeneration and pathological fibrosis</p> Conclusion <p>The pleura can be regarded as a dynamic signaling niche that extends beyond its traditional structural role. We propose the pleural microenvironment as a regulatory interface governing the balance between tissue regeneration and fibrotic remodeling. Targeting pleural-derived signaling networks may provide novel therapeutic opportunities for restoring physiological repair while limiting fibrotic progression in chronic lung diseases.</p> Graphical abstract <p></p>