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<p>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.</p>

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The FTO-YTHDF2 axis drives immune evasion and tumor progression in hepatocellular carcinoma via m6A-dependent FLAD1 regulation

  • 期刊论文

  • 发表日期：

    2025年8月19日

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  • Chen Xu,
  • Liangjun Jiang,
  • Xianzhou Lu,
  • Wei Li

摘要

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.