Rather a versatile multi-tool than a sword: an integral role of the plasminogen system in health and disease

Proteolysis, the irreversible, hydrolytic cleavage of peptide bonds by proteases, is essential for life. The plasminogen system, one of the central proteolytic systems, regulates diverse physiological pathways, including fibrinolysis, inflammation, wound healing, and tissue remodelling. Beyond its proteolytic functions, the plasminogen system serves as a hub for crosstalk to maintain homeostasis. Yet, its dysregulation, misuse, or hijacking by pathogens can drive pathologies such as hereditary disorders, tumour dissemination, bacterial invasion, and viral priming. This review explores its evolution, structural aspects, activation mechanisms, regulatory pathways, and pharmacological modulation of the plasminogen system, synthesising decades of research with recent advances. We highlight the multifaceted nature of the plasminogen system—as both a guardian of physiological balance and a potential driver of disease—and discuss its components as therapeutic targets and tools.