OLFM4 (olfactomedin 4) is a secreted protein with context-dependent roles in cell proliferation, differentiation, and immune regulation. In gastrointestinal tissues, OLFM4 promotes cancer progression through multiple signaling pathways: it activates the MYH9/GSK3β/β-catenin axis to drive intestinal metaplasia progression toward gastric cancer 1, and in EBV-infected cells, extracellular OLFM4 binds FAT1 to activate YAP signaling via the Hippo pathway, promoting tumor immune evasion by upregulating PD-L1 through MAPK-AP1 23. OLFM4 also regulates intestinal homeostasis by promoting IL-22 production in group 3 innate lymphoid cells through ASK1-p38 MAPK/RORγt signaling, thereby modulating inflammation and pathogen resistance 4. Beyond cancer, OLFM4 expression is critical for intestinal stem cell renewal, as it requires fatty acid oxidation-dependent metabolic pathways 5. In brown adipose tissue, OLFM4 coordinates thermoadaptive innervation by promoting Schwann cell differentiation via BMP7 signaling; OLFM4 deficiency impairs thermogenesis and predisposes to obesity 6. OLFM4 also serves as a potential biomarker for acute kidney injury sub-phenotypes in critical illness 7. These diverse functions highlight OLFM4's role as a pleiotrophic regulator of epithelial-immune-neural crosstalk across multiple tissues.