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      Post-translational protein lactylation modification in health and diseases: a double-edged sword

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          Abstract

          As more is learned about lactate, it acts as both a product and a substrate and functions as a shuttle system between different cell populations to provide the energy for sustaining tumor growth and proliferation. Recent discoveries of protein lactylation modification mediated by lactate play an increasingly significant role in human health (e.g., neural and osteogenic differentiation and maturation) and diseases (e.g., tumors, fibrosis and inflammation, etc.). These views are critically significant and first described in detail in this review. Hence, here, we focused on a new target, protein lactylation, which may be a “double-edged sword” of human health and diseases. The main purpose of this review was to describe how protein lactylation acts in multiple physiological and pathological processes and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for treating different diseases and accelerate translation from bench to bedside.

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          Most cited references128

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Macrophage biology in development, homeostasis and disease.

            Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.
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              Metabolic regulation of gene expression by histone lactylation

              The Warburg effect, originally describing augmented lactogenesis in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, macrophage polarization, and T-cell activation. This phenomenon is intimately linked with multiple diseases including neoplasia, sepsis, and autoimmune diseases 1,2 . Lactate, a compound generated during Warburg effect, is widely known as an energy source and metabolic byproduct. However, its non-metabolic functions in physiology and disease remain unknown. Here we report lactate-derived histone lysine lactylation as a new epigenetic modification and demonstrate that histone lactylation directly stimulates gene transcription from chromatin. In total, we identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce production of lactate through glycolysis that in turn serves as precursor for stimulating histone lactylation. Using bacterially exposed M1 macrophages as a model system, we demonstrate that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, elevated histone lactylation induces homeostatic genes involved in wound healing including arginase 1. Collectively, our results suggest the presence of an endogenous “lactate clock” in bacterially challenged M1 macrophages that turns on gene expression to promote homeostasis. Histone lactylation thus represents a new avenue for understanding the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.
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                Author and article information

                Contributors
                llp0131@126.com
                zhangdk8616@126.com
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                10 January 2024
                10 January 2024
                2024
                : 22
                : 41
                Affiliations
                [1 ]Department of Gastroenterology, Lanzhou University Second Hospital, ( https://ror.org/02erhaz63) Lanzhou, Gansu China
                [2 ]Department of Gastroenterology, Zigong First People’s Hospital, ( https://ror.org/04khs3e04) Zigong, Sichuan China
                [3 ]Department of Gastroenterology, Sichuan Academy of Medical Sciences and Sichuan People’s Hospital, ( https://ror.org/01qh26a66) Chengdu, Sichuan China
                Article
                4842
                10.1186/s12967-023-04842-9
                10777551
                6bf240f7-a0e3-4bf4-8672-450a0fe184f8
                © The Author(s) 2024

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 7 November 2023
                : 27 December 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100018554, Science and Technology Program of Gansu Province;
                Award ID: 2022RCXM071
                Award ID: 20YF8FA078
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007764, Lanzhou Science and Technology Bureau;
                Award ID: 2018-RC-76
                Award Recipient :
                Categories
                Review
                Custom metadata
                © BioMed Central Ltd., part of Springer Nature 2024

                Medicine
                lactate,lactylation,post-translational modification
                Medicine
                lactate, lactylation, post-translational modification

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