β-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. Consequently, during lipopolysaccharide-induced septic liver injury, SOD2 Kbhb suppressed NLRP3 inflammasome activation in macrophages and protected hepatocytes from apoptosis. Collectively, our findings identify the β-OHB-SOD2-Kbhb axis as a previously unrecognized antioxidant pathway and highlight its therapeutic potential in sepsis.