Long-chain acylcarnitine deficiency promotes hepatocarcinogenesis.
10.1016/j.apsb.2025.01.017
- Author:
Kaifeng WANG
1
;
Zhixian LAN
1
;
Heqi ZHOU
1
;
Rong FAN
1
;
Huiyi CHEN
1
;
Hongyan LIANG
1
;
Qiuhong YOU
1
;
Xieer LIANG
1
;
Ge ZENG
1
;
Rui DENG
1
;
Yu LAN
1
;
Sheng SHEN
1
;
Peng CHEN
2
;
Jinlin HOU
1
;
Pengcheng BU
3
;
Jian SUN
1
Author Information
1. State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Clinical Research Center for Viral Hepatitis; Guangdong Provincial Key Laboratory of Viral Hepatitis Research; Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
2. Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
3. Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
- Publication Type:Journal Article
- Keywords:
Acetyl coenzyme A;
CUT&Tag;
Chemoprevention;
H3K14;
Hepatocellular carcinoma;
KLF6;
Long-chain acylcarnitine;
Metabolomics
- From:
Acta Pharmaceutica Sinica B
2025;15(3):1383-1396
- CountryChina
- Language:English
-
Abstract:
Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.
