REG4 (regenerating family member 4) is a calcium-independent lectin with mannose-binding specificity capable of functioning in acidic environments 1. It plays dual roles in gastrointestinal homeostasis and pathological processes. In normal physiology, REG4 maintains gut immune homeostasis by shaping the microbiota composition; specifically, REG4-associated bacteria metabolize linoleic acid into conjugated linoleic acid (CLA), which promotes IL-35 expression in macrophages via Gαq/11-mediated STAT1/4 signaling 2. In acute and chr1 pancreatitis, REG4 exerts protective effects by limiting inflammation, reducing mitochondrial cell death, and promoting cellular regeneration through interaction with its receptor Extl3 and modulation of the CXCL12/CXCR4 axis 3. Conversely, REG4 is aberrantly overexpressed in multiple cancers (colorectal, gastric, pancreatic, ovarian, prostate, lung) and associates with poor prognosis 1. In cancer cells, REG4 binds CD44 and activates regulated intramembrane proteolysis, releasing the CD44 intracytoplasmic domain to drive proliferation and stem cell properties through D-type cyclin and pluripotency factor (Klf4, Sox2) induction 4. REG4 promotes apoptosis resistance, metastasis, and chemotherapy/radiotherapy resistance through multiple pathways including EGFR/Akt/AP-1 signaling and upregulation of antiapoptotic genes 5 6. Thus, REG4 functions as both a protective mediator in inflammatory conditions and a pro-tumorigenic factor in malignancies, representing a potential diagnostic and therapeutic target.