High mobility group box 1 protein (HMGB1) and cold-inducible RNA-binding protein (CIRP), as unique signaling molecules in sepsis, jointly activate the toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and HIF-1a signaling pathways within macrophages, thereby enhancing both glycolytic metabolism and the pro-inflammatory response. The gene discussed is TLR4; the disease is Sepsis.