Qingchangligan formula alleviates acute liver injury by attenuating extracellular histone-associated inflammation

Qingchangligan formula (QCLGF) is a traditional Chinese medicine that has exhibited remarkable clinical efficacy for patients with acute-on-chronic liver failure (ACLF). However, the hepatoprotective mechanisms of QCLGF are not completely understood. Extracellular histones were recently identified as the novel inflammatory mediators involved in the pathogenesis of acute liver injury. This study aimed to investigate whether QCLGF provides hepatoprotection by targeting extracellular histones. We showed that QCLGF significantly improved the survival rate of the ConA-treated mice, ameliorated hepatotoxicity, and markedly decreased the levels of extracellular histones and the associated cytokines. We further demonstrated that QCLGF attenuated systemic inflammation by inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, exogenous histones induced a significant HL-7702 cell damage, which could be prevented by administration of QCLGF. Lastly, we observed that extracellular histones and the associated cytokines were consistently lower in ACLF patients receiving conventional medical therapy plus QCLGF than in patients receiving only conventional medical therapy. Collectively, these results provide evidence that QCLGF has therapeutic potentials for treating ACLF, which may be due to its ability to interfere with extracellular histone-mediated cellular damage and systemic inflammation.