Abstract
l-Lactate has emerged as a crucial metabolic intermediate, moving beyond its traditional view as a mere waste product. The recent discovery of l-lactate-driven protein lactylation as a post-translational modification has unveiled a pathway that highlights the role of lactate in cellular signalling. In this Perspective, we explore the enzymatic and metabolic mechanisms underlying protein lactylation and its impacts on both histone and non-histone proteins in the contexts of physiology and diseases. We discuss growing evidence suggesting that this modification regulates a wide range of cellular functions and is involved in various physiological and pathological processes, such as cell-fate determination, development, cardiovascular diseases, cancer and autoimmune disorders. We propose that protein lactylation acts as a pivotal mechanism, integrating metabolic and signalling pathways to enable cellular adaptation, and highlight its potential as a therapeutic target in various diseases.
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Fig. 1: The biochemistry of protein lactylation.
Fig. 2: Regulation of DNA activity by protein lactylation.
Fig. 3: Regulation of cell metabolism and signalling by protein lactylation.
Fig. 4: Protein lactylation in cardiovascular diseases.
Fig. 5: Protein lactylation in tumours.
Fig. 6: Protein lactylation in autoimmune uveitis.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (32270822), the Peking-Tsinghua Center for Life Science, the State Key Laboratory of Gene Function and Modulation Research, the School of Life Sciences at Peking University, the Qidong-SLS Innovation Fund and the Clinical Medicine Plus X-Young Scholars Project at Peking University (PKU2024LCXQ025), the Fundamental Research Funds for the Central Universities to D.Z. We were grateful to the members of the Zhang lab for their assistance in proofreading the manuscript. We sincerely apologize to researchers whose important contributions could not be cited owing to space limitations. All figures were created using BioRender.com.
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Yuwei Tang
Present address: Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, USA
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State Key Laboratory of Gene Function and Modulation Research, School of Life Sciences, Peking University, Beijing, China
Haowen Ren, Yuwei Tang & Di Zhang
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
Di Zhang
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H.R. constructed the figures. D.Z. conceived the manuscript and D.Z., H.R. and Y.T. jointly wrote the manuscript.
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Ren, H., Tang, Y. & Zhang, D. The emerging role of protein l-lactylation in metabolic regulation and cell signalling. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01259-0
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Received:14 August 2024
Accepted:03 March 2025
Published:02 April 2025
DOI:https://doi.org/10.1038/s42255-025-01259-0
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