GCN5–ERK lactylation–phosphorylation loop amplifies lactate-driven cancer progression
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Abstract
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.
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- Authors
- Huang, B., Jin, M., Cui, G., Wang, Z., Wang, F., Chen, M., Zhu, L., Li, Y., Yang, X., Li, R., Wu, J., Zhai, L., He, Y., Yang, J., Ding, X., Wang, Q., Xv, Z., Ouyang, Y., Li, J., Yang, Y., Li, K., Lou, Z., Mer, G., Zhang, J., Chen, Y., Yuan, J., & Zhong, C.
- Affiliations
- Tongji University (CN)
- Mayo Clinic (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- First Affiliated Hospital of Nanchang University (CN)
- Corresponding author
- Zhang, Jing
- Chen, Yuping
- Yuan, Jian
- Zhong, Chunlong
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2026-01-13
- Volume
- 22
- Issue
- 4
- Pages
- 634-648
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W7123363086
- Cited by
- 24
- References
- 6
- Citations by year
- 2026: 24
- FWCI
- 76.92
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81571184, 81771332, 82172820, 82271406)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- GCN5, lactate, Warburg effect, MAPK signaling, ERK1/2 phosphorylation, positive feedback loop, cell-penetrating peptides, KRAS-mutant cancer, tumor growth
- MeSH terms
- Animals, Humans, Neoplasms, Phosphorylation, Disease Progression, Lactic Acid, MAP Kinase Signaling System, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, p300-CBP Transcription Factors, Mice
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