Differential metabolites facilitate metabolic dysfunction-associated fatty liver disease malignancy via immune evasion and M2-polarized macrophages

doi:10.3748/wjg.v32.i24.117849

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Jun 28, 2026; 32(24): 117849
Published online Jun 28, 2026. doi: 10.3748/wjg.v32.i24.117849

Differential metabolites facilitate metabolic dysfunction-associated fatty liver disease malignancy via immune evasion and M2-polarized macrophages

Jie Yang, Wen-Li Sai, Xiao-Xiao Xia, Hao Tang, Min Xu, Qun Xie, Deng-Fu Yao, Min Yao

Jie Yang, Department of Biology, Life Science School of Nantong University, Nantong 226009, Jiangsu Province, China

Wen-Li Sai, Min Xu, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China

Xiao-Xiao Xia, Qun Xie, Department of Infectious Diseases, Haian People’s Hospital, Haian 226600, Jiangsu Province, China

Hao Tang, Min Yao, Department of Immunology, Medical School of Nantong University, Nantong University, Nantong 226001, Jiangsu Province, China

Co-first authors: Jie Yang and Wen-Li Sai.

Co-corresponding authors: Min Yao and Deng-Fu Yao.

Author contributions: Yang J and Sai WL contributed equally as co-first authors; Yang J, Sai WL, and Tang H conceived the study and analyzed and interpreted the data; Yang J, Xia XX, and Xu M performed the experiments; Sai WL performed statistical analysis and bioinformatics; Tang H and Xie Q acquired the material and data; Yao M and Yao DF acquired funding, wrote the manuscript, and made equal contribution as co-corresponding authors. All authors have read and approved the final manuscript.

Supported by National Natural Science Foundation of China, No. 32470985 and No. 81673241; Nantong Science and Technology Project, No. MS2024051; Nantong Federation for the Prevention and Control of Infectious Diseases, No. NTCRB2025016; and Nantong Health Commission of China, No. QN2025064.

Institutional review board statement: This study was approved by the Institutional Review Board of Affiliated Hospital of Nantong University, No. 2024-L178.

Institutional animal care and use committee statement: All procedures of the experimental research were approved by the Animal Care and Use Committee of Nantong University, No. P20230327-001.

Conflict-of-interest statement: The authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: All the data presented in this study are available from the corresponding author upon reasonable request.

Corresponding author: Deng-Fu Yao, MD, PhD, Postdoc, Professor, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, No. 20 West Temple Road, Nantong 226001, Jiangsu Province, China. yaodf@ahnmc.com

Received: December 18, 2025
Revised: January 16, 2026
Accepted: March 4, 2026
Published online: June 28, 2026
Processing time: 171 Days and 22.4 Hours

Abstract

BACKGROUND

Differential metabolites (DMs) are associated with metabolic dysfunction-associated fatty liver disease (MAFLD) malignant transformation. However, their underlying mechanisms remain to be identified.

AIM

To investigate the dynamic alterations of DMs, carnitine palmitoyl transferase-II (CPT-II) and immune cells during MAFLD malignancy.

METHODS

A rat model was constructed with high fat diet plus 2-fluorenylacetamide to induce hepatocyte malignancy. Livers were divided into MAFLD, metabolic dysfunction-associated steatohepatitis, liver cirrhosis (LC) and hepatocellular carcinoma (HCC) groups based on hematoxylin and eosin staining, with normal rats as control. DMs were identified via RNA transcriptomics or metabolomics. Proteins were detected by western blotting, and immune cells were analyzed by single-cell sequencing.

RESULTS

Model livers with obvious lipid accumulation and cells were examined during MAFLD malignancy from inflammation or necrosis to LC or HCC and exhibited a pathological alteration of nuclear pleomorphism, disordered arrangement and a progressive decrease in CPT-II activity. The number of DMs was 131 in MAFLD, 134 in metabolic dysfunction-associated steatohepatitis, 27 in liver fibrosis/LC, and 130 in HCC, respectively. Cyclin B1 and cyclin-dependent kinase 1 were involved in the P53 pathway and cell cycle, and they held key positions in the protein interaction network, which involved metabolic regulation of cell response to stimuli. DMs, such as phosphatidylcholine or sphingomyelin in steroid biosynthesis, were significantly related to MAFLD malignancy. Mechanistically, liver immune cells undergo dynamic changes in a fat-rich microenvironment, with decreased T cell abundance and increased programmed death ligand 1 expression and M2-polarized macrophages.

CONCLUSION

Downregulated CPT-II aggravates the accumulation of metabolites associated with MAFLD malignancy via immune evasion and M2-polarized macrophages.

Keywords: Differential metabolites; Carnitine palmitoyl transferase-II; Immune escape; Differentially expressed genes; M2-polarized macrophages; Hepatocarcinogenesis

Core Tip: Dynamic alterations in metabolites and immune cell populations provide insight into metabolic dysfunction-associated fatty liver disease-related malignancy. These changes include loss of carnitine palmitoyltransferase II activity and significant alterations in phosphatidylcholines and sphingomyelins associated with steroid biosynthesis. Additionally, the fat-rich microenvironment is characterized by immune modulation, including reduced T-cell function, increased in programmed death ligand-1 (PD-L1) expression that facilitates immune escape, and enrichment of M2-polarized macrophages, all of which contribute to the progression of metabolic dysfunction-associated fatty liver disease-related malignancy.