LY96 is a transmembrane glycoprotein that functions as a critical co-receptor in innate immune signaling. Its primary role is binding bacterial lipopolysaccharide (LPS) and cooperating with TLR4 to initiate immune responses against Gram-negative bacteria 12. LY96 also cooperates with TLR2 in detecting cell wall components from both Gram-positive and Gram-negative bacteria 3. Mechanistically, LY96 enhances TLR4-dependent NF-κB activation, and cells require both LY96 and TLR4 expression to mount effective LPS-induced immune responses 4. Beyond canonical immunology, LY96 demonstrates broad disease relevance. Pan-cancer analysis reveals LY96 upregulation in most cancer types with prognostic significance, correlating with tumor mutation burden, microsatellite instability, and immune infiltration patterns 5. LY96 serves as a shared diagnostic biomarker in inflammatory conditions including psoriatic arthritis, rheumatoid arthritis 6, diabetic nephropathy 7, systemic lupus erythematosus, and periodontal disease 8. In osteoarthritis, the CD14/TLR4/LY96 pathway regulates macrophage polarization and inflammation 9. Notably, in mesenchymal glioblastoma, LY96 promotes stem cell maintenance through autocrine signaling and drives macrophage polarization toward a tumor-promoting state through paracrine mechanisms 10. Clinically, LY96 represents a potential therapeutic target across multiple disease contexts, with modulation of LY96 signaling showing promise in reducing inflammation and improving outcomes in cancer, autoimmune, and degenerative diseases.