LY96 (lymphocyte antigen 96, also known as MD-2) is a co-receptor essential for innate immune sensing of bacterial lipopolysaccharide (LPS). It binds LPS directly and cooperates with TLR4 to activate NF-κB-dependent inflammatory responses to Gram-negative bacteria, as well as with TLR2 in responses to cell wall components from Gram-positive bacteria. Cells expressing both LY96 and TLR4, but not TLR4 alone, respond to LPS stimulation. Beyond its canonical role in infection defense, LY96 has emerged as a multi-functional regulator in chr8 inflammatory and neoplastic diseases. In rheumatoid arthritis, LY96 expression is elevated and drives pro-inflammatory M1 macrophage polarization through TLR4/NF-κB signaling; transcriptional repression of LY96 by FOXA2 reduces disease severity 1. In glioblastoma, mesenchymal stem cells secrete LY96, which activates an autocrine NF-κB loop promoting self-renewal while simultaneously polarizing tumor-associated macrophages toward a mesenchymal phenotype 2. Pan-cancer analyses show LY96 is upregulated in most cancers, correlates with progression stage, and associates with immune infiltration patterns and drug resistance 3. LY96 is recognized as a shared diagnostic biomarker in psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus, and periodontal disease 4, 5. The TLR4 antagonist eritoran tetrasodium has been approved and represents a clinical application targeting this pathway, though direct LY96 inhibition shows promise in preclinical models of osteoarthritis and glioblastoma.