Hepatocyte CBX2 Safeguards Hepatic Lipid Homeostasis by Elevating Ca²⁺-CaMKK2-AMPK Signaling to Counter MASLD.
9 affiliations
- 1Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, China.
- 2Department of Hyperbaric Oxygen, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, China.
- 3MOE Key Laboratory of Metabolism and Molecular Medicine & Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai, China.
- 4Department of Anesthesiology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China.
- 5Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
- 6Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- 7State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China.
- 8Tianjin Key Laboratory of Cellular Homeostasis and Disease, Key Department of Physiology and Pathophysiology, Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China.
- 9Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of adults and lacks effective pharmacological therapies. Here, we identify Chromobox 2 (CBX2), a Polycomb-associated chromatin regulator, as a previously unrecognized regulator of hepatic lipid homeostasis. CBX2 expression is markedly reduced in hepatocytes from patients with MASLD, multiple mouse models (db/db, ob/ob, HFD, and HFHC), and steatotic hepatocytes in vitro. Hepatocyte-specific CBX2 overexpression ameliorates hepatic steatosis, improves glucose metabolism, and suppresses inflammation, whereas CBX2 deficiency exacerbates these metabolic disturbances. Mechanistically, CBX2 enhances H3K4me3 enrichment at the Orai1 promoter, promoting Orai1 transcription and increasing intracellular Ca²⁺ levels. Elevated Ca²⁺ activates the CaMKK2-AMPK signaling pathway, leading to ACC phosphorylation, inhibition of de novo lipogenesis (FAS, ACC, and SCD-1), enhancement of fatty acid oxidation (PPARα and CPT-1a), and suppression of NF-κB/JNK-mediated inflammation. Genetic and pharmacological interventions further establish the necessity of this Ca²⁺-CaMKK2-AMPK axis for CBX2-mediated metabolic protection. Collectively, our findings reveal a CBX2-driven metabolic regulatory circuit and highlight CBX2 and its downstream signaling pathway as potential therapeutic targets for MASLD.
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BibTeX
@article{wei2026hepatocyte,
title = {{Hepatocyte CBX2 Safeguards Hepatic Lipid Homeostasis by Elevating Ca²⁺-CaMKK2-AMPK Signaling to Counter MASLD.}},
author = {Xiang Wei and Li Lin and Xiuyun Wang and Hui Du and Menglong Zhang and Kechao Tang and Han Gao and Xinrui Xie and Jingya Gao and Xu Wang and Zhenglin Wang and Siwei Huang and Lei Zhang and Fang Gu and Gong-Hong Wei and Yinliang Qi and Wei Chen and Yongsheng Chang and Huabing Zhang},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.78372},
url = {https://europepmc.org/article/MED/42893482},
note = {CC BY},
}
RIS
TY - JOUR
TI - Hepatocyte CBX2 Safeguards Hepatic Lipid Homeostasis by Elevating Ca²⁺-CaMKK2-AMPK Signaling to Counter MASLD.
AU - Xiang Wei
AU - Li Lin
AU - Xiuyun Wang
AU - Hui Du
AU - Menglong Zhang
AU - Kechao Tang
AU - Han Gao
AU - Xinrui Xie
AU - Jingya Gao
AU - Xu Wang
AU - Zhenglin Wang
AU - Siwei Huang
AU - Lei Zhang
AU - Fang Gu
AU - Gong-Hong Wei
AU - Yinliang Qi
AU - Wei Chen
AU - Yongsheng Chang
AU - Huabing Zhang
PY - 2026
DA - 2026/10/18
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.78372
UR - https://europepmc.org/article/MED/42893482
AB - Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of adults and lacks effective pharmacological therapies. Here, we identify Chromobox 2 (CBX2), a Polycomb-associated chromatin regulator, as a previously unrecognized regulator of hepatic lipid homeostasis. CBX2 expression is markedly reduced in hepatocytes from patients with MASLD, multiple mouse models (db/db, ob/ob, HFD, and HFHC), and steatotic hepatocytes in vitro. Hepatocyte-specific CBX2 overexpression ameliorates hepatic steatosis, improves glucose metabolism, and suppresses inflammation, whereas CBX2 deficiency exacerbates these metabolic disturbances. Mechanistically, CBX2 enhances H3K4me3 enrichment at the Orai1 promoter, promoting Orai1 transcription and increasing intracellular Ca²⁺ levels. Elevated Ca²⁺ activates the CaMKK2-AMPK signaling pathway, leading to ACC phosphorylation, inhibition of de novo lipogenesis (FAS, ACC, and SCD-1), enhancement of fatty acid oxidation (PPARα and CPT-1a), and suppression of NF-κB/JNK-mediated inflammation. Genetic and pharmacological interventions further establish the necessity of this Ca²⁺-CaMKK2-AMPK axis for CBX2-mediated metabolic protection. Collectively, our findings reveal a CBX2-driven metabolic regulatory circuit and highlight CBX2 and its downstream signaling pathway as potential therapeutic targets for MASLD.
SN - 2198-3844
ER -