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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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The FTO-YTHDF2 axis drives immune evasion and tumor progression in hepatocellular carcinoma via m6A-dependent FLAD1
Chen Xu1, Liangjun Jiang2, Xianzhou Lu1
1Department of Hepatobiliary Surgery, The Affiliated Nahua Hospital, Hengyang Medical School, University of South China, No. 336 Dongfeng South Road, Zhuhui District, Hengyang, 421002, Hunan Province, China.
Abstract:
This study investigates the molecular mechanism by which the FTO-YTHDF2 axis regulates FLAD1 expression through m6A modification to drive immune evasion and tumor progression in hepatocellular carcinoma (HCC). By bioinformatics analysis of TCGA-HCC data, FLAD1 was identified as a key oncogenic driver, with elevated expression in HCC tissues and cells. Functional experiments revealed that FLAD1 knockdown suppressed HCC proliferation, migration, invasion, and PD-L1 expression while enhancing CD8 + T cell cytotoxicity (evidenced by increased IFN-γ, TNF-α, and LDH release). Mechanistically, FTO, an m6A demethylase, upregulated FLAD1 by removing m6A marks to counteract YTHDF2-mediated mRNA degradation. In vivo, FTO silencing reduced tumor growth and PD-L1 levels while elevating pro-inflammatory cytokines, and the effects negated by YTHDF2 knockdown. These findings establish that the FTO-YTHDF2 axis promotes HCC immune evasion and tumor progression via m6A-dependent FLAD1 stabilization, highlighting the axis as a therapeutic target to disrupt tumorigenesis and restore anti-tumor immunity.
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