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<p>The Warburg effect leads to increased lactate production and promotes cancer progression but the underlying mechanisms remain unclear. Here, we found that lactate activates the MAPK pathway through ERK lactylation, which promotes cancer progression. We identified GCN5 as the lactyltransferase responsible for ERK lactylation. Activated ERK phosphorylates GCN5, increasing its lactyltransferase activity toward ERK and establishing a positive feedback loop that amplifies lactate-mediated cancer progression. We provide evidence that lactylation of ERK at residue K231 weakens its interaction with MEK, thereby promoting ERK dimerization and activation. We developed a cell-penetrating peptide that specifically inhibits ERK lactylation. This peptide impairs tumor growth in <i>KRAS</i>-mutant cancer models. Taken together, our findings reveal a molecular mechanism by which lactate accelerates cancer progression through the ERK–GCN5 lactylation–phosphorylation cascade and suggest a strategy to disrupt ERK lactylation in RAS–ERK-driven cancers.</p><p></p>

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GCN5–ERK lactylation–phosphorylation loop amplifies lactate-driven cancer progression

  • 期刊论文

  • 发表日期：

    2026年1月13日

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  • Bingsong Huang,
  • Mingpeng Jin,
  • Gaofeng Cui,
  • Zhe Wang,
  • Feng Wang,
  • Mu Chen,
  • Lei Zhu,
  • Yunxuan Li,
  • Xiaoning Yang,
  • Rui Li,
  • Jinhuan Wu,
  • Linhui Zhai,
  • Yiming He,
  • Jie Yang,
  • Xin Ding,
  • Qianwen Wang,
  • Zhen Xv,
  • Yaobing Ouyang,
  • Jiale Li,
  • Yangbohui Yang,
  • Ke Li,
  • Zhenkun Lou,
  • Georges Mer,
  • Jing Zhang,
  • Yuping Chen,
  • Jian Yuan,
  • Chunlong Zhong

摘要

The Warburg effect leads to increased lactate production and promotes cancer progression but the underlying mechanisms remain unclear. Here, we found that lactate activates the MAPK pathway through ERK lactylation, which promotes cancer progression. We identified GCN5 as the lactyltransferase responsible for ERK lactylation. Activated ERK phosphorylates GCN5, increasing its lactyltransferase activity toward ERK and establishing a positive feedback loop that amplifies lactate-mediated cancer progression. We provide evidence that lactylation of ERK at residue K231 weakens its interaction with MEK, thereby promoting ERK dimerization and activation. We developed a cell-penetrating peptide that specifically inhibits ERK lactylation. This peptide impairs tumor growth in KRAS-mutant cancer models. Taken together, our findings reveal a molecular mechanism by which lactate accelerates cancer progression through the ERK–GCN5 lactylation–phosphorylation cascade and suggest a strategy to disrupt ERK lactylation in RAS–ERK-driven cancers.