Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD.

1. Cell Rep. 2025 Mar 25;44(3):115350. doi: 10.1016/j.celrep.2025.115350. Epub 2025 Feb 25. Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD. Li J(1), Chen X(2), Song S(3), Jiang W(4), Geng T(5), Wang T(6), Xu Y(6), Zhu Y(7), Lu J(8), Xia Y(9), Wang R(10). Author information: (1)Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210046, China; Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu 210029, China. (2)Department of Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210029, China. (3)Nanjing Lupine (YuShanDou) Biomedical Research Institute, Nanjing, Jiangsu 210046, China. (4)Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu 210029, China. (5)Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China. (6)Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210046, China. (7)Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210046, China. Electronic address: zhuyqscu@163.com. (8)Department of Intensive Care Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China. Electronic address: lujun@njucm.edu.cn. (9)Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu 210029, China; NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Electronic address: yx_xia@njmu.edu.cn. (10)Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu 210046, China; Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan 410219, China. Electronic address: rongwang@nnu.edu.cn. Erratum in Cell Rep. 2025 Mar 25;44(3):115465. doi: 10.1016/j.celrep.2025.115465. Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by metabolic dysfunction and inflammation burden, involving a significant enhancement of cellular glycolytic activity. Here, we elucidate how a positive feedback loop in liver macrophages drives MASLD pathogenesis and demonstrate that disrupting this cycle mitigates metabolic stress and macrophage M1 activation during MASLD. We detect elevated expression of hexokinase 2 (HK2) and H3K18la in liver macrophages from patients with MASLD and MASLD mice. This lactate-dependent histone lactylation promotes glycolysis and liver macrophage M1 polarization by enriching the promoters of glycolytic genes and activating transcription. Ultimately, the HK2/glycolysis/H3K18la positive feedback loop exacerbates the vicious cycle of enhancing metabolic dysregulation and histone lactylation and the inflammatory phenotype of liver macrophages. Myeloid-specific deletion of Hk2 or pharmacological inhibition of the transcription factor HIF-1α significantly disrupts this deleterious cycle. Therefore, our study illustrates that targeting this amplified pathogenic loop may offer a promising therapeutic strategy for MASLD. Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.celrep.2025.115350 PMID: 40014451 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests The authors declare no competing interests.