Extracellular histone H3 induces macrophage inflammation in acute liver failure via HDAC2 activation and PKM2 subcellular relocalization.

Acute liver failure (ALF) is a life-threatening clinical syndrome with limited therapeutic options beyond liver transplantation. Extracellular histones, released from dying or activated cells as damage-associated molecular patterns (DAMPs), exert concentration-dependent cytotoxicity and can activate immune cells to trigger inflammatory responses. In the present study, we investigated the impact of extracellular histone H3 on macrophage function during ALF and explored the underlying mechanisms using both in vivo and in vitro models. Extracellular histones stimulation significantly increased inflammation levels in mice. In vitro, H3-treated macrophages adopted a proinflammatory phenotype and exhibited impaired phagocytic capacity. Moreover, H3 stimulation promoted nuclear translocation of PKM2, enhanced glycolytic activity, and upregulated HDAC2 expression in macrophages. Pharmacological inhibition of HDAC2 partially suppressed PKM2 nuclear localization and attenuated macrophage-driven inflammatory responses. Finally, molecular docking and immunofluorescence assays confirmed a direct interaction between HDAC2 and PKM2. Collectively, our findings demonstrate that extracellular histone H3 drives a proinflammatory macrophage phenotype by modulating HDAC2 expression and PKM2 subcellular localization, thereby accelerating the progression of ALF.