The study presents a novel pharmacological approach to suppress inflammatory gene expression by targeting the recognition of acetylated histones by Bromodomains (BET) proteins. The compound I-BET, a synthetic mimic of acetylated histones, was identified and optimized for in vivo experiments. I-BET disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, thereby conferring protection against LPS-induced endotoxic shock and bacteria-induced sepsis. The compound's selectivity is based on its ability to bind selectively to BET proteins, which are involved in the assembly of histone acetylation-dependent chromatin complexes that regulate inflammatory gene expression. In vitro and in vivo experiments demonstrated that I-BET down-regulates a specific subset of LPS-inducible genes, including cytokines and chemokines, without affecting housekeeping genes or viability of macrophages. The compound's therapeutic potential was further validated in mouse models of endotoxic shock and sepsis, where it significantly reduced mortality and inflammation. These findings suggest that synthetic compounds targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.The study presents a novel pharmacological approach to suppress inflammatory gene expression by targeting the recognition of acetylated histones by Bromodomains (BET) proteins. The compound I-BET, a synthetic mimic of acetylated histones, was identified and optimized for in vivo experiments. I-BET disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, thereby conferring protection against LPS-induced endotoxic shock and bacteria-induced sepsis. The compound's selectivity is based on its ability to bind selectively to BET proteins, which are involved in the assembly of histone acetylation-dependent chromatin complexes that regulate inflammatory gene expression. In vitro and in vivo experiments demonstrated that I-BET down-regulates a specific subset of LPS-inducible genes, including cytokines and chemokines, without affecting housekeeping genes or viability of macrophages. The compound's therapeutic potential was further validated in mouse models of endotoxic shock and sepsis, where it significantly reduced mortality and inflammation. These findings suggest that synthetic compounds targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.