INAVA (innate immunity activator) is a pattern recognition receptor (PRR)-signaling amplifier expressed in macrophages and intestinal myeloid cells. Upon stimulation by diverse PRRs (NOD2, TLRs 2/3/4/5/7/9), INAVA associates with 14-3-3ζ to recruit and activate MAP kinases and NF-κB signaling, amplifying cytokine secretion and bacterial clearance 1. INAVA exhibits dual competing functions: at lateral membranes, its DUF3338 domain (CUPID) binds the cytohesin ARNO to stabilize adherens junctions and barrier function; in the cytosol, INAVA forms biomolecular condensates containing ubiquitin and βTrCP2 E3 ligase, amplifying TRAF6-dependent polyubiquitination and inflammatory signaling 12. INAVA has well-established disease relevance: genome-wide association studies identified INAVA as a risk locus for inflammatory bowel disease, primary biliary cholangitis, and anterior uveitis 34. Beyond immune regulation, INAVA mRNA in ovarian cancer-derived extracellular vesicles activates fibroblasts by modulating HMGA2 phosphorylation-ubiquitination crosstalk 5, and TGF-β3 upregulates INAVA in natural killer cells to enhance interferon-γ signaling and anti-tumor cytotoxicity 6. In breast cancer, INAVA is a SMAD3-dependent TGF-β target promoting migration, invasion, and self-renewal 7. These findings suggest INAVA as a pleiotropic regulator linking intestinal barrier homeostasis to systemic immunity and cancer biology.