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Peer-reviewedCC BY-NC-NDSignal Transduction and Targeted Therapy

Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications

  • Yue Yang1,2
  • Ying He3
  • Ziyi Zhang1
  • Y L Zhang1
  • Rui Gao1
  • Ke Du1
  • Yan Wu1,2
  • Ji Wu4,5
  • Minjie Wei6,7,8
  • Mingyan Liu9
9 affiliations
  1. 1Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China
  2. 2Drug and Food Inspection and Testing Center, China Medical University, Shenyang, China
  3. 3The First Department of Medical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
  4. 4Shenyang Key Laboratory of Chronic Disease Assessment and Nutritional Intervention for Heart and Brain, Shenyang Medical College, Shenyang, China. [email protected]
  5. 5The Second Affiliated Hospital of Shenyang Medical College, Shenyang, China. [email protected]
  6. 6Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China. [email protected]
  7. 7Drug and Food Inspection and Testing Center, China Medical University, Shenyang, China. [email protected]
  8. 8Liaoning Medical Diagnosis and Treatment Center, Shenyang, China. [email protected]
  9. 9Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, China. [email protected]
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Abstract

Protein lysine lactylation (Kla) is a newly identified post-translational modification (PTM), in which lactyl groups are transferred to specific lysine residues in proteins. As a crucial intermediary between cellular metabolism and epigenetic regulation, Kla immensely increases the functional diversity of the proteome. This intriguing modification extends beyond histones to non-histone proteins, signaling molecules, enzymes, and substrates. In addition to enzymatic L-lactylation utilizing lactate as a lactyl donor and involving enzymes including writers (lactyltransferases), readers (lactylation-binding enzymes), erasers (delactylases), and lactyl-coenzyme A (lactyl-CoA) synthases, non-enzymatic D-lactylation derived from the glyoxalase II substrate S-D-lactoylglutathione (SLG) has also been identified. Emerging evidence underscores the molecular significance of Kla, including gene transcriptional activation, protein stability, enzyme activity, protein‒protein interactions, protein subcellular translocation, crosstalk with other PTMs, RNA modification, epigenetic instability, and phase separation, in orchestrating diverse biological processes. Functionally, Kla plays a fundamental role in physiology, such as somatic cell reprogramming, as well as embryonic, neural, and cochlear development, by regulating gene expression, cell cycle progression, and signal transduction. Conversely, dysregulated Kla renders extensive impacts on the pathogenesis of various diseases, including cancer, neuropsychiatric disorders, cardiovascular and ophthalmic diseases, and immunoinflammatory and metabolic dysregulation, through modulating immune homeostasis, metabolic adaptation, and epigenetic remodeling. This review systematically elucidates the molecular regulatory mechanisms and biological significance of Kla while comprehensively summarizing its involvement in both physiology and pathology. Furthermore, we emphasize the translational potential of Kla as a diagnostic or prognostic biomarker and therapeutic target, offering novel insights for future research and development of innovative therapeutic strategies.

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Cite

BibTeXRIS
BibTeX
@article{yang2026protein,
  title = {{Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications}},
  author = {Yue Yang and Ying He and Ziyi Zhang and Y L Zhang and Rui Gao and Ke Du and Yan Wu and Ji Wu and Minjie Wei and Mingyan Liu},
  journal = {Signal Transduction and Targeted Therapy},
  year = {2026},
  month = jul,
  doi = {10.1038/s41392-026-02757-7},
  url = {https://doi.org/10.1038/s41392-026-02757-7},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications
AU  - Yue Yang
AU  - Ying He
AU  - Ziyi Zhang
AU  - Y L Zhang
AU  - Rui Gao
AU  - Ke Du
AU  - Yan Wu
AU  - Ji Wu
AU  - Minjie Wei
AU  - Mingyan Liu
PY  - 2026
DA  - 2026/07/06
JO  - Signal Transduction and Targeted Therapy
DO  - 10.1038/s41392-026-02757-7
UR  - https://doi.org/10.1038/s41392-026-02757-7
AB  - Protein lysine lactylation (Kla) is a newly identified post-translational modification (PTM), in which lactyl groups are transferred to specific lysine residues in proteins. As a crucial intermediary between cellular metabolism and epigenetic regulation, Kla immensely increases the functional diversity of the proteome. This intriguing modification extends beyond histones to non-histone proteins, signaling molecules, enzymes, and substrates. In addition to enzymatic L-lactylation utilizing lactate as a lactyl donor and involving enzymes including writers (lactyltransferases), readers (lactylation-binding enzymes), erasers (delactylases), and lactyl-coenzyme A (lactyl-CoA) synthases, non-enzymatic D-lactylation derived from the glyoxalase II substrate S-D-lactoylglutathione (SLG) has also been identified. Emerging evidence underscores the molecular significance of Kla, including gene transcriptional activation, protein stability, enzyme activity, protein‒protein interactions, protein subcellular translocation, crosstalk with other PTMs, RNA modification, epigenetic instability, and phase separation, in orchestrating diverse biological processes. Functionally, Kla plays a fundamental role in physiology, such as somatic cell reprogramming, as well as embryonic, neural, and cochlear development, by regulating gene expression, cell cycle progression, and signal transduction. Conversely, dysregulated Kla renders extensive impacts on the pathogenesis of various diseases, including cancer, neuropsychiatric disorders, cardiovascular and ophthalmic diseases, and immunoinflammatory and metabolic dysregulation, through modulating immune homeostasis, metabolic adaptation, and epigenetic remodeling. This review systematically elucidates the molecular regulatory mechanisms and biological significance of Kla while comprehensively summarizing its involvement in both physiology and pathology. Furthermore, we emphasize the translational potential of Kla as a diagnostic or prognostic biomarker and therapeutic target, offering novel insights for future research and development of innovative therapeutic strategies.
SN  - 2059-3635
SN  - 2095-9907
ER  -