Plasminogen Activation System and Fibroblasts: Impact on Tissue Remodeling, Disease, and Organ Homeostasis

The interplay between fibroblasts and the plasminogen activation system is increasingly recognized as a central driver of fibrosis, thrombosis, and cancer progression. Fibroblasts, as key producers of extracellular matrix (ECM), regulate tissue integrity, repair, and remodeling. Through their interactions with urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and plasmin, fibroblasts influence ECM degradation, cell migration, angiogenesis, and inflammation. Dysregulation of this crosstalk contributes to persistent fibrosis in organs such as lung, liver, kidney, and heart, and facilitates stromal remodeling in cancer. Notably, paradoxical effects are evident-for example, PAI-1 promotes fibroblast survival while inducing apoptosis in alveolar epithelial cells, highlighting context-dependent actions. This review summarizes recent findings across major organs and tissue-specific mechanisms. We also discuss the emerging therapeutic potential of targeting fibroblast-plasminogen interactions, including PAI-1 inhibitors, uPA/uPAR antagonists, and natural compounds, alongside challenges in clinical translation. This review critically integrates mechanistic and organ-specific evidence, including plasminogen receptors as essential mediators of pericellular plasmin generation with uPA/tPA/PAI-1 signaling, across lung, skin, kidney, liver, heart, and cancer contexts. These findings position fibroblasts as central coordinators of fibrinolysis-fibrosis crosstalk and highlight therapeutic opportunities targeting this integrated network.