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<p>Hepatocellular carcinoma (HCC) progression is driven by cancer stem cells (CSCs) with self-renewal and immune evasion capacities. Here, we identify a novel HIF-1α/YTHDF2/PFKL axis that orchestrates metabolic reprogramming in myeloid-derived suppressor cells (MDSCs) to sustain CSC malignancy. Bioinformatics and TCGA analyses revealed HIF-1α and YTHDF2 overexpression correlated with poor HCC prognosis. Mechanistically, HIF-1α binds the YTHDF2 promoter under hypoxia, activating its transcription (validated by ChIP and luciferase assays). YTHDF2, an m6A “reader,” stabilizes PFKL mRNA—a glycolytic rate-limiting enzyme—by recognizing m6A sites (predicted by SRAMP, confirmed via MeRIP/RIP). Functional assays demonstrated that YTHDF2 knockdown reduced PFKL expression, suppressed MDSC glycolysis (decreased ECAR, lactate/ATP production), and attenuated CD8⁺T cell inhibition. Conversely, YTHDF2 overexpression amplified these effects. In vitro, HIF-1α-silenced MDSCs impaired CSC spherogenesis and PD-L1 expression, rescued by PFKL overexpression. In vivo, HIF-1α knockdown inhibited tumor growth and CD8⁺T cell infiltration, while PFKL restoration reversed these phenotypes. Our study unveils HIF-1α-driven m6A modification as a critical link between MDSC metabolism and CSC immune evasion, proposing the HIF-1α/YTHDF2/PFKL axis as a therapeutic target for HCC.</p> Graphical Abstract <p></p>

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Hypoxia-Induced m6A modification via YTHDF2 stabilizes PFKL to fuel MDSC Glycolysis and hepatocellular carcinoma progression

  • 期刊论文

  • 发表日期：

    2025年11月13日

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  • Ziqi Guo,
  • Yuying Huang,
  • Xiaoling Dong,
  • Linyan Shen,
  • Fuguo Yan,
  • Cheng Yang

摘要

Hepatocellular carcinoma (HCC) progression is driven by cancer stem cells (CSCs) with self-renewal and immune evasion capacities. Here, we identify a novel HIF-1α/YTHDF2/PFKL axis that orchestrates metabolic reprogramming in myeloid-derived suppressor cells (MDSCs) to sustain CSC malignancy. Bioinformatics and TCGA analyses revealed HIF-1α and YTHDF2 overexpression correlated with poor HCC prognosis. Mechanistically, HIF-1α binds the YTHDF2 promoter under hypoxia, activating its transcription (validated by ChIP and luciferase assays). YTHDF2, an m6A “reader,” stabilizes PFKL mRNA—a glycolytic rate-limiting enzyme—by recognizing m6A sites (predicted by SRAMP, confirmed via MeRIP/RIP). Functional assays demonstrated that YTHDF2 knockdown reduced PFKL expression, suppressed MDSC glycolysis (decreased ECAR, lactate/ATP production), and attenuated CD8⁺T cell inhibition. Conversely, YTHDF2 overexpression amplified these effects. In vitro, HIF-1α-silenced MDSCs impaired CSC spherogenesis and PD-L1 expression, rescued by PFKL overexpression. In vivo, HIF-1α knockdown inhibited tumor growth and CD8⁺T cell infiltration, while PFKL restoration reversed these phenotypes. Our study unveils HIF-1α-driven m6A modification as a critical link between MDSC metabolism and CSC immune evasion, proposing the HIF-1α/YTHDF2/PFKL axis as a therapeutic target for HCC.

Graphical Abstract