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

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subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS PROTEIN LACTYLATION IN CANCER: MECHANISMS AND POTENTIAL THERAPEUTIC IMPLICATIONS Article Open

access 24 March 2025 LYSINE L-LACTYLATION IS THE DOMINANT LACTYLATION ISOMER INDUCED BY GLYCOLYSIS Article Open access 19 July 2024 MECHANISMS OF METABOLISM-COUPLED PROTEIN MODIFICATIONS

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Google Scholar  Download references 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. AUTHOR INFORMATION Author notes * Yuwei Tang Present address: Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI, USA AUTHORS

AND AFFILIATIONS * 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 Authors * Haowen Ren View author publications You can

also search for this author inPubMed Google Scholar * Yuwei Tang View author publications You can also search for this author inPubMed Google Scholar * Di Zhang View author publications You

can also search for this author inPubMed Google Scholar CONTRIBUTIONS H.R. constructed the figures. D.Z. conceived the manuscript and D.Z., H.R. and Y.T. jointly wrote the manuscript.

CORRESPONDING AUTHOR Correspondence to Di Zhang. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Metabolism_

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Ren, H., Tang, Y. & Zhang, D. The emerging role of protein l-lactylation in metabolic regulation and cell signalling. _Nat Metab_ 7,

647–664 (2025). https://doi.org/10.1038/s42255-025-01259-0 Download citation * Received: 14 August 2024 * Accepted: 03 March 2025 * Published: 02 April 2025 * Issue Date: April 2025 * DOI:

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