2. Academic Validation
  3. β-Hydroxybutyrate ameliorates lipopolysaccharide-induced liver injury through β-hydroxybutyrylation of the SOD2 protein in mice

β-Hydroxybutyrate ameliorates lipopolysaccharide-induced liver injury through β-hydroxybutyrylation of the SOD2 protein in mice

  • Redox Biol. 2025 Dec:88:103949. doi: 10.1016/j.redox.2025.103949.
Ya-Ping Bai 1,  Yan Zhang 2,  Zhi-Yuan Chen 3,  Kai Li 4,  De-Guo Wang 5,  Shu-Jun Wan 6,  Cui-Wei Zhang 7,  Yue Sun 8,  Zhi-Chao Li 9,  Kun Lv 10,  Lei Zha 11,  Xiang Kong 12
Affiliations

Affiliations

  • 1 Department of pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241003, China; Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China. Electronic address: [email protected].
  • 2 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China; Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China. Electronic address: [email protected].
  • 3 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China. Electronic address: [email protected].
  • 4 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China. Electronic address: [email protected].
  • 5 Department of Gerontology, Geriatric endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China; National Clinical Research Center for Geriatric Diseases, Anhui Provincial Sub-center, Wuhu, 241001, China. Electronic address: [email protected].
  • 6 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China. Electronic address: [email protected].
  • 7 Department of Gerontology, Geriatric endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China; National Clinical Research Center for Geriatric Diseases, Anhui Provincial Sub-center, Wuhu, 241001, China. Electronic address: [email protected].
  • 8 Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China. Electronic address: [email protected].
  • 9 Department of Gerontology, Geriatric endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China; National Clinical Research Center for Geriatric Diseases, Anhui Provincial Sub-center, Wuhu, 241001, China. Electronic address: [email protected].
  • 10 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China. Electronic address: [email protected].
  • 11 Department of Respiratory Medicine, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China. Electronic address: [email protected].
  • 12 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China; Department of Gerontology, Geriatric endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, China; National Clinical Research Center for Geriatric Diseases, Anhui Provincial Sub-center, Wuhu, 241001, China. Electronic address: [email protected].
PMID: 41319591 DOI: 10.1016/j.redox.2025.103949
Abstract

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.

Keywords

Apoptosis; Lysine β-hydroxybutyrylation (kbhb); NLRP3 inflammasome; Superoxide dismutase 2 (SOD2); β-Hydroxybutyrate (β-OHB).

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