PLAU (plasminogen activator, urokinase) is a serine protease that cleaves the zymogen plasminogen to generate active plasmin, a key enzyme in fibrinolysis and extracellular matrix remodeling. Beyond its classical coagulation role, PLAU functions as a ligand for the PLAUR receptor, activating signaling pathways that regulate cell migration, adhesion, and immune responses 12. Mechanistically, PLAU operates through multiple pathways. It regulates fibroblast differentiation and extracellular matrix production via TGFβ1-mediated myofibroblast differentiation 3, and activates Hippo-YAP signaling in fibroblasts upon PLAUR binding 2. PLAU is upregulated by hypoxia-inducible factor 1α (HIF1A) under hypoxic conditions, with nuclear translocation of the mitophagy protein NIX enhancing YY1 binding to the PLAU promoter 2. Gene expression is post-transcriptionally regulated by the miR-455-3p/PLAU axis 4 and the JPX/miR-193b-3p/PLAU axis 5. Clinically, elevated PLAU associates with pathological fibrosis in skin scars 3, rheumatoid arthritis 1, and liver fibrosis 4. PLAU serves as a diagnostic biomarker in Alzheimer's disease urinary extracellular vesicles 6 and Sjögren's syndrome 7. In lung adenocarcinoma, hypoxia-driven PLAU activation promotes fibroblast-mediated immunosuppression and immunotherapy resistance 2. Therapeutic PLAU inhibition shows promise in reducing fibrosis and enhancing anti-tumor immunity 32.