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Updated: Sep 19, 2026

In Vitro Cultivation Techniques for Modeling Liver Organogenesis, Building Assembloids, and Designing Synthetic Tissues using Human Cell Lines
Published on: April 18, 2025
IL-11 drives Treg cell differentiation by activating the MBD3/APOH-mediated fatty acid oxidation axis to promote
Yang Gao1,2, Xijuan Yao2, Xing Huang3
1Cancer Center, Department of Interventional Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
Background:
The immunosuppressive tumor microenvironment (TME) represents a major barrier to effective hepatocellular carcinoma (HCC) therapy. While interleukin-11 (IL-11) has been implicated in cancer progression, its immunomodulatory functions and underlying mechanisms in HCC remain poorly understood.
Methods:
We evaluated IL-11 expression and its clinical relevance using data from public databases and clinical HCC specimens. Functional effects of IL-11 were assessed through in vitro cell culture models and in vivo orthotopic tumor experiments in mice. Regulatory T (Treg) cell differentiation and TME composition were analyzed via flow cytometry and immunohistochemistry. Molecular mechanisms were explored using Western blotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation, and metabolic assays, focusing on the IL-11/methyl-CpG binding domain protein 3 (MBD3)/apolipoprotein H (APOH) pathway.
Results:
IL-11 was significantly overexpressed in HCC tissues and correlated with poor patient survival. Functionally, IL-11 enhanced the malignant phenotypes of HCC cells in vitro and in vivo , whereas its knockdown suppressed tumor migration and growth. Importantly, IL-11 increased the proportion of Treg cells in the HCC microenvironment by driving their differentiation, thereby fostering an immunosuppressive TME. Mechanistically, IL-11 upregulated MBD3, which transcriptionally repressed APOH. This downregulation activated the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ (PPARγ)-mediated fatty acid oxidation (FAO) pathway, and pharmacological inhibition of FAO effectively reversed IL-11-induced Treg differentiation and tumor growth.
Conclusion:
We have identified a novel IL-11/MBD3/APOH/FAO regulatory axis that promotes HCC progression by enhancing Treg cell differentiation and establishing an immunosuppressive microenvironment. These results nominate IL-11 as a promising therapeutic target for HCC immunotherapy and shed new light on the metabolic basis of immune evasion in liver cancer.
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