2. Academic Validation
  3. β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein

β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein

  • Cell Death Dis. 2024 Dec 3;15(12):874. doi: 10.1038/s41419-024-07268-3.
Ya-Ping Bai # 1 2,  Yu-Jie Xing # 1,  Tao Ma # 1,  Kai Li 1,  Teng Zhang 3,  De-Guo Wang 4 5,  Shu-Jun Wan 1,  Cui-Wei Zhang 4 5,  Yue Sun 3,  Meng-Yan Wang 6,  Guo-Dong Wang 6,  Wen-Jun Pei 7,  Kun Lv 8,  Yan Zhang 9 10,  Xiang Kong 11 12 13 14
Affiliations

Affiliations

  • 1 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, China.
  • 2 College of Life Sciences, Anhui Normal University, Wuhu, China.
  • 3 Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China.
  • 4 Department of Gerontology, Geriatric Endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Wuhu, China.
  • 5 National Clinical Research Center for Geriatric Diseases, Anhui Provincial Sub-center, Wuhu, China.
  • 6 School of Pharmacy, Wannan Medical College, Wuhu, China.
  • 7 Anhui Province Key Laboratory of Biological Macro-molecules Research, Wannan Medical College, Wuhu, China.
  • 8 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, China. lvkun315@126.com.
  • 9 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, China. yanyan0921@sina.com.
  • 10 Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China. yanyan0921@sina.com.
  • 11 Anhui Provincial Key Laboratory of Non-coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, China. xiangkong@wnmc.edu.cn.
  • 12 College of Life Sciences, Anhui Normal University, Wuhu, China. xiangkong@wnmc.edu.cn.
  • 13 Department of Gerontology, Geriatric Endocrinology unit, The First Affiliated Hospital of Wannan Medical College, Wuhu, China. xiangkong@wnmc.edu.cn.
  • 14 National Clinical Research Center for Geriatric Diseases, Anhui Provincial Sub-center, Wuhu, China. xiangkong@wnmc.edu.cn.
  • # Contributed equally.
PMID: 39627223 DOI: 10.1038/s41419-024-07268-3
Abstract

β-Hydroxybutyrate (β-OHB), the primary ketone body, is a bioactive metabolite that acts as both an energy substrate and a signaling molecule. Recent studies found that β-OHB inhibits the production of pro-inflammatory cytokines in macrophages, but its underlying molecular mechanisms have not yet been fully elucidated. Lysine β-hydroxybutyrylation (Kbhb), a post-translational modification mediated by β-OHB, plays a key role in regulating the expression and activity of modified proteins. However, whether macrophages undergo protein Kbhb and whether Kbhb modification regulates macrophage polarization remains largely unknown. In this study, treatment with β-OHB and ketone ester significantly decreased the lipopolysaccharide (LPS)-induced enhancement of the M1 phenotype of mouse bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and peritoneal macrophages (PMs) in vitro and in vivo. Moreover, β-OHB treatment induced global protein Kbhb, which is associated with the regulation of macrophage M1 polarization. Proteome-wide Kbhb analysis in β-OHB-treated BMDMs revealed 3469 Kbhb modification sites within 1549 proteins, among which interleukin-12-responding proteins were significantly upregulated. Our results indicated that β-OHB regulated M1 macrophage polarization by inducing Kbhb modification of the signal transducer and activator of transcription 1 (STAT1) K679 site, which inhibited its LPS-induced phosphorylation and transcription. Altogether, our study demonstrated the presence of a widespread Kbhb landscape in the β-OHB-treated macrophages and provided novel insights into the anti-inflammatory effects of β-OHB.

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