Abstract

Background Sepsis remains a leading cause of mortality in intensive care units, with endotoxemia-induced hepatic inflammation being a major contributor to multiorgan failure. Bromodomain and extraterminal domain (BET) proteins are key epigenetic regulators of inflammation. While the BET inhibitor JQ1 shows protective effects in sepsis models, its toxicity limits translational application. NHWD-870, a next-generation BET inhibitor with improved potency and safety, has not been evaluated in septic liver injury. Methods Eight-week-old male C57BL/6 mice were challenged with lipopolysaccharide (LPS) to induce endotoxemia and treated with NHWD-870 1 hour before LPS challenge. Survival rate was assessed and 0.5mg/kg was selected as the optimal dose. Liver injury and inflammation were assessed by histopathology, serum biochemistry, ELISA, RT-qPCR, and immunohistochemistry. In vitro, primary mouse hepatocytes (PMHs) and bone marrow-derived macrophages (BMDMs) were stimulated with LPS to examine NHWD-870 effects on cytokine production and macrophage polarization. Results NHWD-870 improved survival in lethal LPS challenge and attenuated LPS induced ALT/AST elevations and hepatic inflammatory infiltration. Serum and hepatic IL6, TNFα, and MCP1 were reduced after NHWD-870; IL6 suppression at 12 h exceeded JQ1. NHWD-870 decreased hepatic macrophage and neutrophil infiltration and no obvious histopathological abnormalities were observed in the major organs at the active dose. In vitro, NHWD-870 dose dependently reduced LPS induced cytokine expression in PMH and BMDM and inhibited macrophage M1 polarization (CD86, iNOS). BRD4 and STAT1 expression increased after LPS; NHWD 870 suppressed both. Conclusion NHWD-870 ameliorates endotoxemia-associated hepatic inflammation and improves survival in mice, at least in part via suppression of BRD4-STAT1 signaling and inhibition of macrophage M1 polarization. Further preclinical development is warranted.