ZG16 (zymogen granule protein 16) is a secretory glycoprotein primarily produced in organs with high enzyme secretion, functioning as a lectin with glycan-binding capacity 1. While traditionally characterized as playing a role in protein trafficking within the Golgi apparatus and zymogen granule formation 2, ZG16 has emerged as a critical regulator of mucosal immunity and tumor suppression. ZG16 is secreted by intestinal goblet cells as a mucus component and binds microbial pathogens, contributing to the first-line defense of the gastrointestinal tract 21. The protein contains a redox-active CXXC motif enabling disulfide bond formation with sulfhydryl oxidases in the Golgi and mucus 1. Clinically, ZG16 downregulation correlates with colorectal cancer progression; miR-196a-mediated loss of ZG16 promotes cancer stemness and growth 3. ZG16 knockout mice exhibit compromised intestinal barrier integrity, dysbiotic microbiota, and increased susceptibility to ulcerative colitis and inflammation-related colorectal cancer 4. ZG16 also impacts pulmonary inflammation through gut microbiota-derived metabolites 4. In hepatocellular carcinoma and pancreatic cancer, ZG16 overexpression suppresses tumor progression and promotes M1 polarization of tumor-associated macrophages while inhibiting immunosuppressive M2 polarization 56. Mechanistically, ZG16 promotes SNX9 degradation through ITCH-mediated ubiquitination in hepatocellular carcinoma 6.