PLAU (plasminogen activator, urokinase) encodes a serine protease that converts the zymogen plasminogen into active plasmin, initiating fibrinolysis and regulating extracellular matrix remodeling. Beyond its canonical role in coagulation, PLAU functions as a cell-surface receptor ligand that regulates integrin-mediated signaling, cell migration, and tissue remodeling through multiple pathways including TGF-β/Smad signaling and the JAK-STAT axis. PLAU is implicated in several pathological processes. In head and neck squamous cell carcinoma (HNSCC), elevated PLAU expression correlates with poor survival and promotes perineural invasion through interactions with nerve growth factor, facilitating tumor malignancy 1. In pancreatic ductal adenocarcinoma, PLAU knockdown inhibits cell proliferation and survival 2. Within the tumor microenvironment of anorectal malignant melanoma, PLAU-expressing fibroblasts (iCAF_PLAU) enhance cancer stem cell properties and mediate immunosuppression 3. PLAU also drives HNC progression via STAT3 signaling, with elevated expression linked to reduced overall and disease-free survival 4. Beyond cancer, PLAU participates in hypertrophic scar formation through TGF-β1-mediated myofibroblast differentiation; topical PLAU inhibitors reduced fibrotic markers in vivo 5. In idiopathic pulmonary fibrosis, apolipoprotein E attenuates fibrosis by engaging PLAU alongside LRP1 to suppress TGF-β/Smad signaling 6. Clinically, urokinase (a uPA product) is approved as a thrombolytic agent. The LXR agonist RGX-104 represents a therapeutic avenue for enhancing endogenous PLAU suppression of pulmonary fibrogenesis 6.