HGFAC (hepatocyte growth factor activator) is a serine endopeptidase that functions as a critical link between tissue injury and repair 1. As a circulating zymogen, HGFAC is activated by thrombin and kallikrein-related peptidases to cleave the inactive hepatocyte growth factor precursor (proHGF) at Arg494-Val495, generating active disulfide-linked HGF heterodimers that initiate MET receptor signaling 1. HGFAC also activates macrophage-stimulating protein, a RON ligand involved in tissue remodeling 1. A Crohn's disease-associated variant (R509H) impairs MSP activation, disrupting damage-sensing pathways that coordinate wound-associated epithelial cell differentiation and fibroblast-mediated tissue restitution 2. As a ChR4-regulated hepatokine, HGFAC enhances glucose and lipid homeostasis, potentially through hepatic PPARγ activation 3. Genetically predicted HGFAC levels inversely associate with inflammatory bowel disease and ulcerative colitis risk 4, and decreased expression correlates with poor prognosis in hepatocellular carcinoma, associated with promoter hypermethylation 5. HGFAC emerges as a promising therapeutic target for gastrointestinal inflammation and metabolic disorders 6 7.