IL-11 drives Treg cell differentiation by activating the MBD3/APOH-mediated fatty acid oxidation axis to promote hepatocellular carcinoma

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.