{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPINT1, also known as hepatocyte growth factor activator inhibitor‐1 (HAI‐1), is a membrane‐bound, Kunitz‐type serine protease inhibitor that plays an essential role in maintaining the balance of pericellular proteolysis. It functions by binding and reversibly inhibiting several trypsin‐like serine proteases—including hepatocyte growth factor activator (HGFA), matriptase, hepsin, and prostasin—to regulate the proteolytic activation of growth factors such as pro–HGF, as well as by acting as a cell‐surface reservoir for active proteases. The inhibitor is synthesized as an integral membrane protein that may be shed from the cell surface under inflammatory or tissue injury conditions, a process that modulates its inhibitory activity and regulates signal transduction pathways at epithelial surfaces."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various cancer models, alterations in SPINT1 expression or its ratio relative to target proteases such as matriptase are closely linked to tumor progression, invasion, and metastasis. Loss or down‐regulation of SPINT1 in carcinoma cells has been shown to trigger epithelial–mesenchymal transition (EMT) through deregulated proteolytic activity and signaling cascades (involving substrates like pro–HGF and PAR‐2) that ultimately enhance motility and invasiveness. In several epithelial malignancies—including pancreatic, prostate, and cervical cancers—the aberrant expression of SPINT1 is correlated with reduced cell–cell adhesion, increased protease activity on the cell surface, and a more aggressive tumor phenotype."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in protease inhibition, SPINT1 is also involved in fine‐tuning cellular responses in diverse tissues. Structural and biochemical studies reveal that its configuration and shedding dynamics are critical for modulating interactions with both membrane‐bound and soluble proteases, thereby influencing downstream signaling pathways such as HGF/MET and p38 MAPK. In normal tissues including skin, placenta, and the gastrointestinal tract—and during processes like differentiation, inflammation, and tissue repair—the regulatory actions of SPINT1 help maintain epithelial integrity. Moreover, the emerging understanding of its molecular interactions has spurred interest in targeting SPINT1–protease networks as a therapeutic strategy in conditions ranging from placental insufficiency to cancer metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "H Kataoka, T Shimomura, T Kawaguchi, et al. 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