biostudies-literatureBai YPAnhui Provincial Key Research and Development PlanNational Natural Science Foundation of China103949https://www.ebi.ac.uk/biostudies/studies/S-EPMC12704266biostudies-literatureUnknown88Septic liver injury is a major complication of sepsis, driven in part by oxidative stress-induced macrophage inflammasome activation and hepatocyte apoptosis. β-Hydroxybutyrate (β-OHB), a key ketone body, induces lysine β-hydroxybutyrylation (Kbhb), a novel post-translational modification, yet its role in septic liver injury remains unclear. In this study, we demonstrated that β-OHB markedly increased Kbhb modification of superoxide dismutase 2 (SOD2), a mitochondrial antioxidant enzyme, in both macrophages and hepatocytes. Mechanistically, β-OHB promoted Kbhb at lysine 68 of SOD2, thereby preventing ubiquitin-proteasome-mediated degradation, and then stabilizing the protein, which enhanced its enzymatic activity, and reduced mitochondrial reactive oxygen species accumulation. ConsequentlyRedox biologyβ-Hydroxybutyrate ameliorates lipopolysaccharide-induced liver injury through β-hydroxybutyrylation of the SOD2 protein in mice.PMC1270426681970699AHWJ2024Aa10024Wang DGLv KLi ZCZhang YChen ZYBai YPZha LLi KWan SJZhang CWSun YKong Xfalseβ-Hydroxybutyrate ameliorates lipopolysaccharide-induced liver injury through β-hydroxybutyrylation of the SOD2 protein in mice.Septic liver injury is a major complication of sepsis, driven in part by oxidative stress-induced macrophage inflammasome activation and hepatocyte apoptosis. β-Hydroxybutyrate (β-OHB), a key ketone body, induces lysine β-hydroxybutyrylation (Kbhb), a novel post-translational modification, yet its role in septic liver injury remains unclear. In this study, we demonstrated that β-OHB markedly increased Kbhb modification of superoxide dismutase 2 (SOD2), a mitochondrial antioxidant enzyme, in both macrophages and hepatocytes. Mechanistically, β-OHB promoted Kbhb at lysine 68 of SOD2, thereby preventing ubiquitin-proteasome-mediated degradation, and then stabilizing the protein, which enhanced its enzymatic activity, and reduced mitochondrial reactive oxygen species accumulation. Consequently2025-01-01T00:00:00Z2025 Dec2026-06-07T05:20:12.052Z2026-06-07T03:07:01.458ZS-EPMC127042664131959110.1016/j.redox.2025.103949