SPINT2 encodes a serine protease inhibitor that functions primarily as an inhibitor of hepatocyte growth factor activator (HGFAC) 1, preventing conversion of pro-HGF to bioactive HGF and thereby suppressing HGF/c-MET signaling 2. SPINT2 also inhibits plasmin, kallikrein, and membrane-anchored proteases including matriptase and prostasin 345. In healthy lung, SPINT2 marks a major fibroblast population 6, while its loss correlates with myofibroblast differentiation in systemic sclerosis-associated interstitial lung disease. SPINT2 functions as a tumor suppressor across multiple cancers. In cervical carcinoma and high-grade gliomas, the SPINT2 gene is frequently silenced through aberrant promoter methylation, with HPV infection promoting this epigenetic alteration 78. SPINT2 reactivation reduces cancer cell viability, migration, and invasion 2. In gallbladder cancer, SPINT2 specifically promotes ferroptosis by stabilizing ACSL4 protein through prevention of NEDD4L-mediated ubiquitination, with low SPINT2 expression associated with poor prognosis 9. Germline SPINT2 mutations cause congenital sodium diarrhea with atresias 10. Mendelian randomization identifies SPINT2 as a potential therapeutic target in prostate cancer 11.