Extracellular histone H3 induces METosis in acute liver failure by regulating the NRF2/HO-1/NQO1 pathway-mediated...

Acute liver failure (ALF) is a life-threatening condition marked by extensive hepatocyte death and the subsequent release of damage-associated molecular patterns (DAMPs), notably extracellular histone H3, which contributes to severe complications such as multiple organ failure. Although extracellular histone H3 is known to exert direct cytotoxic effects, its role in macrophage extracellular trap formation (METosis)-a distinct form of macrophage cell death-remains poorly defined. This study aims to elucidate the involvement of extracellular histone H3 in METosis during ALF and to explore the underlying molecular mechanisms. Using both in vivo and in vitro models, we found that extracellular histone H3 induced METosis and aggravated liver injury. Histone H3 exposure also elevated oxidative stress levels, accompanied by marked downregulation of NRF2, HO-1, and NQO1, as revealed by Western blot analysis. Importantly, treatment with the antioxidant 4-hydroxyphenylacetic acid (4-HPA) mitigated oxidative stress, restored the expression of NRF2, HO-1, and NQO1, and reduced histone H3-induced METs formation in vitro. In summary, our findings demonstrate that extracellular histone H3 promotes METosis and exacerbates ALF, which is closely associated with the suppression of the NRF2/HO-1/NQO1 antioxidant pathway, thereby enhancing oxidative stress. These results provide new insights into the pathogenic role of extracellular histone H3 in ALF and suggest potential therapeutic avenues targeting redox homeostasis.