bims-prolim 2025-03-16 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–03–16
twenty-one papers selected by
Bruna Martins Garcia, CABIMER

Regulation of Adaptive Immunity by Lipid Post-translational Modifications.
Insulin regulates lymphatic endothelial integrity via palmitoylation.
Tissue-Specific Profiling of O-GlcNAcylated Proteins in Drosophila Using TurboID-CpOGAM.
The role of protein lactylation: A kaleidoscopic post-translational modification in cancer.
The role of lactate metabolism and lactylation in pulmonary arterial hypertension.
Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies.
Advances in targeting protein S-palmitoylation in tumor immunity and therapy.
Attenuating ABHD17 isoforms augments the S-acylation and function of NOD2 and a subset of Crohn's disease-associated NOD2 variants.
The Role of Lactate and Lactylation in the Dysregulation of Immune Responses in Psoriasis.
Evidence for Functional Regulation of the KLHL3/WNK Pathway by O-GlcNAcylation.
Lactate: A key regulator of the immune response.
Characterization of substrate distribution and functional implication of lysine acylations in Staphylococcus aureus.
Acetylation: a new target for protein degradation in cancer.
L- and D-Lactate: unveiling their hidden functions in disease and health.
Lactylation: a promising therapeutic target in ischemia-reperfusion injury management.
Regulation of autophagy: Insights into O-GlcNAc modification mechanisms.
Pharmacologically targeting fatty acid synthase-mediated de novo lipogenesis alleviates osteolytic bone loss by directly inhibiting osteoclastogenesis through suppression of STAT3 palmitoylation and ROS signaling.
Tumor Glycosylation: A Main Player in the Modulation of Immune Responses.
Protein Glycosylation Patterns Shaped By the IRE1-XBP1s Arm of the Unfolded Protein Response.
N-Acetyltransferase 10 Promotes Gastric Cancer Progression by Mediating the N4-Acetylcytidine Modification of Lactate Dehydrogenase A.
Class I histone deacetylases catalyze lysine lactylation.

Immune Netw. 2025 Feb;25(1): e11

Regulation of Adaptive Immunity by Lipid Post-translational Modifications.

Jonathan R Mattingly, Aimee Wu, Autumn G York.

  The burgeoning field of immunometabolism highlights the interdependence between metabolic programs and efficacious immune responses. The current understanding that cellular metabolic remodeling is necessary for a competent adaptive immune response, along with acutely sensitive methodologies such as high-performance liquid chromatography/mass spectrometry and advanced proteomics, have ushered in a renaissance of lipid- and metabolic-based scientific inquiries. One facet of recent interest examines how lipids function as post-translational modifications (PTMs) and their resulting effects on adaptive immune responses. The goal of this review is to establish a fundamental understanding of these protein modifications and highlight recent findings that underscore the importance of continued investigation into lipids as PTMs.

Keywords:  Adaptive immunity; Myristoylation; Palmitoylation; Prenylation

DOI:  https://doi.org/10.4110/in.2025.25.e11
J Lipid Res. 2025 Mar 11. pii: S0022-2275(25)00035-5. [Epub ahead of print] 100775

Insulin regulates lymphatic endothelial integrity via palmitoylation.

Silvia Gonzalez-Nieves, Xiaochao Wei, Simon Guignard, Thi Nguyen, Jay McQuillan, Qiang Zhang, Jinsong Zhang, Reagan M McGuffee, David A Ford, Clay F Semenkovich, Vincenza Cifarelli.

  Lipid metabolism plays a critical role in lymphatic endothelial cell (LEC) development and vessel maintenance. Altered lipid metabolism is associated with loss of lymphatic vessel integrity, which compromises organ function, protective immunity, and metabolic health. Thus, understanding how lipid metabolism affects LECs is critical for uncovering the mechanisms underlying lymphatic dysfunction. Protein palmitoylation, a lipid-based post-translational modification, has emerged as a critical regulator of protein function, stability, and interaction networks. Insulin, a master regulator of systemic lipid metabolism, also regulates protein palmitoylation. However, the role of insulin-driven palmitoylation in LEC biology remains unexplored. To examine the role of palmitoylation in LEC function, we generated the first palmitoylation proteomics profile in human LECs, validated insulin-regulated targets and determined the role of palmitoylation in LEC barrier function. In unstimulated condition, palmitoylation occurred primarily on proteins involved in vesicular and membrane trafficking, and in translation initiation. Insulin treatment, instead, enriched palmitoylation of proteins involved in LEC integrity, namely junctional proteins such as claudin 5, along with small GTPases and ubiquitination enzymes. We also investigated the role of the long-chain fatty acid transporter CD36, a major mediator of palmitate uptake into cells, in regulating optimal lymphatic protein palmitoylation. CD36 silencing in LECs increased by 2-fold palmitoylation of proteins involved in inflammation and immune cell activation. Overall, our findings provide novel insights into the intricate relationship between lipid modification and LEC function, suggesting that insulin and palmitoylation play a critical role in lymphatic endothelial function.

Keywords:  CD36; CD63; LECs; claudin 5; insulin; palmitoylation

DOI:  https://doi.org/10.1016/j.jlr.2025.100775
Bio Protoc. 2025 Mar 05. 15(5): e5234

Tissue-Specific Profiling of O-GlcNAcylated Proteins in Drosophila Using TurboID-CpOGAM.

Qin Lei, Haibin Yu, Fang Chen, Kai Yuan.

  Protein O-GlcNAcylation is a prevalent and dynamic post-translational modification that targets a multitude of nuclear and cytoplasmic proteins. Through the modification of diverse substrates, O-GlcNAcylation plays a pivotal role in essential cellular processes, including transcription, translation, and protein homeostasis. Dysregulation of O-GlcNAc homeostasis has been implicated in a variety of diseases, including cardiovascular diseases, cancer, and neurodegenerative diseases. Studying O-GlcNAcylated proteins in different tissues is crucial to understanding the pathogenesis of these diseases. However, identifying phenotype-relevant candidate substrates in a tissue-specific manner remains unfeasible. We developed a novel tool for the analysis of O-GlcNAcylated proteins, combining a catalytically inactive CpOGA mutant CpOGACD and TurboID proximity labeling technology. This tool converts O-GlcNAc modifications into biotin labeling, enabling the enrichment and mass spectrometry (MS) identification of O-GlcNAcylated proteins in specific tissues. Meanwhile, TurboID-CpOGADM, which carries two point mutations that inactivate both its catalytic and binding activities toward O-GlcNAc modification, was used as a control to differentiate O-GlcNAc-independent protein-protein interactions. We have successfully used TurboID-CpOGACD/DM (TurboID-CpOGAM) to enrich O-GlcNAc proteins in Drosophila combining the UAS/Gal4 system. Our protocol provides a comprehensive workflow for tissue-specific enrichment of candidate O-GlcNAcylated substrates and offers a valuable tool for dissecting tissue-specific O-GlcNAcylation functions in Drosophila. Key features • Innovative approach to studying O-GlcNAcylation: Combines a catalytically inactive CpOGA mutant (CpOGACD), TurboID proximity labeling technology, and the UAS/Gal4 system for tissue-specific analysis. • Tissue-specific focus: Enables enrichment and mass spectrometry (MS) identification of O-GlcNAcylated proteins in specific tissues of Drosophila. • Biotin labeling conversion: Converts O-GlcNAc modifications into biotin tags, facilitating downstream enrichment and analysis. • Powerful tool for understanding the role of O-GlcNAcylation in cellular processes and its involvement in diseases such as cardiovascular diseases, cancer, and neurodegenerative disorders.

Keywords:  Drosophila; Protein O-GlcNAcylation; Tissue-specific analysis; TurboID proximity labeling

DOI:  https://doi.org/10.21769/BioProtoc.5234
Mol Cell. 2025 Mar 05. pii: S1097-2765(25)00142-X. [Epub ahead of print]

The role of protein lactylation: A kaleidoscopic post-translational modification in cancer.

Marta Iozzo, Elisa Pardella, Elisa Giannoni, Paola Chiarugi.

  The recently discovered lysine lactylation represents a critical post-translational modification with widespread implications in epigenetics and cancer biology. Initially identified on histones, lysine lactylation has been also described on non-histone proteins, playing a pivotal role in transcriptional activation, protein function, and cellular processes. Two major sources of the lactyl moiety have been currently distinguished: L-lactyl-CoA (precursor of the L-lactyl moiety) and S-D-lactylglutathione (precursor of the D-lactyl moiety), which enable enzymatic and non-enzymatic mechanisms of lysine lactylation, respectively. Although the specific writers, erasers, and readers of this modification are still unclear, acetyltransferases and deacetylases have been proposed as crucial mediators of lysine lactylation. Remarkably, lactylation exerts significant influence on critical cancer-related pathways, thereby shaping cellular behavior during malignant transformation and the metastatic cascade. Hence, as recent insights into lysine lactylation underscore its growing potential in tumor biology, targeting this modification is emerging as a significant opportunity for cancer treatment.

Keywords:  cancer aggressiveness; histone lactylation; lactyl-CoA; lactylglutathione; non-histone protein lactylation

DOI:  https://doi.org/10.1016/j.molcel.2025.02.011
Respir Res. 2025 Mar 12. 26(1): 99

The role of lactate metabolism and lactylation in pulmonary arterial hypertension.

Tong-Yu Peng, Jun-Mi Lu, Xia-Lei Zheng, Cheng Zeng, Yu-Hu He.

  Pulmonary arterial hypertension (PAH) is a complex and progressive disease characterized by elevated pulmonary artery pressure and vascular remodeling. Recent studies have underscored the pivotal role of metabolic dysregulation and epigenetic modifications in the pathogenesis of PAH. Lactate, a byproduct of glycolysis, is now recognized as a key molecule that links cellular metabolism with activity regulation. Recent findings indicate that, in addition to altered glycolytic activity and dysregulated. Lactate homeostasis and lactylation-a novel epigenetic modification-also play a significant role in the development of PAH. This review synthesizes current knowledge regarding the relationship between altered glycolytic activity and PAH, with a particular focus on the cumulative effects of lactate in pulmonary vascular cells. Furthermore, lactylation, an emerging epigenetic modification, is discussed in the context of PAH. By elucidating the complex interplay between lactate metabolism and lactylation in PAH, this review aims to provide insights into potential therapeutic targets. Understanding these metabolic pathways may lead to innovative strategies for managing PAH and improving patient outcomes. Future research should focus on the underlying mechanisms through which lactylation influences the pathophysiology of PAH, thereby aiding in the development of targeted interventions.

Keywords:  Glycolysis; Lactate; Lactylation; Protein translational modifications; Pulmonary arterial hypertension

DOI:  https://doi.org/10.1186/s12931-025-03163-3
Exp Hematol Oncol. 2025 Mar 08. 14(1): 32

Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies.

Mengqi Lv, Yefei Huang, Yansu Chen, Kun Ding.

  Cancer remains the leading cause of mortality worldwide, and the emergence of drug resistance has made the identification of new therapeutic targets imperative. Lactate, traditionally viewed as a byproduct of glycolysis with limited ATP-producing capacity, has recently gained recognition as a critical signaling molecule. It plays a key role not only in cancer cell metabolism but also in shaping the tumor microenvironment (TME). Histone lysine lactylation, a newly identified post-translational modification, has been shown to influence a range of cellular processes in cancer. Current research focuses on the mechanisms and functions of histone lactylation in cancer, including its role in gene expression regulation, signal transduction, and protein synthesis. However, despite these advancements, there are still plenty of barriers in the quest to unravel the mechanisms of lactylation modification. The emergence of single-cell and spatial transcriptomics may offer valuable insights for selecting targets. This review provides a comprehensive summary of the mechanisms and the applications of lactylation modification in clinical settings. Through a detailed analysis, we identify the key challenges and limitations that exist in the current research landscape. These insights lay the groundwork for future studies by highlighting promising research directions.

Keywords:  Cancer; Lactylation; Metabolic reprogramming; Metastasis; Therapy

DOI:  https://doi.org/10.1186/s40164-025-00622-x
Front Oncol. 2025 ;15 1547636

Advances in targeting protein S-palmitoylation in tumor immunity and therapy.

Miaomiao Han, Yuanhao Lv, Yiyang Chen, Zhaoyi Li, Jiaqi Tian, Hongyan Zhou, Yunlong Wang, Wei Su, Jiateng Zhong.

  S-palmitoylation is a reversible and dynamic post-translational modification of proteins. A palmitoyl group is covalently attached to a cysteine residue of the protein by a thioester link. It regulates the transcription and expression of downstream target genes and cell signaling, influencing cellular functions. Research indicates a substantial correlation between S-palmitoylation and tumorigenesis and immunotherapy, where it plays a pivotal role in modulating T cell activation, cytokine signaling, autophagy, phagocytosis, and death. Moreover, palmitoylation contributes to drug resistance and immunological evasion in tumor cells, enabling them to circumvent the effects of chemotherapeutic drugs and immune surveillance. Inhibitors that target S-palmitoylation have demonstrated significant potential in enhancing the efficacy of tumor immunotherapy, offering a novel strategy for cancer treatment. Nonetheless, obstacles such as inhibitor specificity and efficacy persist, requiring more extensive investigations into the exact mechanisms of S-palmitoylation to develop more effective targeted therapeutics. This article summarizes recent developments in S-palmitoylation concerning tumor immunity and treatment. The article examines the regulatory function of S-palmitoylation, its modifying enzymes in tumor cell signaling, and novel tumor immunotherapies that target S-palmitoylation.

Keywords:  S-palmitoylation; T cells; drug resistance; immune escape; immunotherapy; tumor

DOI:  https://doi.org/10.3389/fonc.2025.1547636
Cell Mol Gastroenterol Hepatol. 2025 Mar 05. pii: S2352-345X(25)00032-3. [Epub ahead of print] 101491

Attenuating ABHD17 isoforms augments the S-acylation and function of NOD2 and a subset of Crohn's disease-associated NOD2 variants.

Charneal L Dixon, Noah R Martin, Micah J Niphakis, Benjamin F Cravatt, Gregory D Fairn.

   BACKGROUND AND AIMS: NOD2 is an intracellular innate immune receptor that detects bacterial peptidoglycan fragments. Although nominally soluble, some NOD2 is associated with the plasma membrane and endosomal compartments for microbial surveillance. This membrane targeting is achieved through post-translational S-acylation of NOD2 by the protein acyltransferase ZDHHC5. Membrane attachment is necessary to initiate a signaling cascade in response to cytosolic peptidoglycan fragments. Ultimately, this signaling results in the production of antimicrobial peptides and proinflammatory cytokines. In most cases, S-acylation is a reversible post-translational modification with removal of the fatty acyl chain catalyzed by one of several acyl protein thioesterases. Deacylation of NOD2 by such an enzyme will displace it from the plasma membrane and endosomes, thus preventing signaling.
METHODS: To identify the enzymes responsible for NOD2 deacylation, we used engineered cell lines with RNA interference and small-molecule inhibitors. These approaches were combined with confocal microscopy, acyl-resin-assisted capture, immunoblotting, and cytokine multiplex assays.
RESULTS: We identified α/β-hydrolase domain-containing protein 17 isoforms (ABHD17A, ABHD17B, and ABHD17C) as the acyl protein thioesterases responsible for NOD2 deacylation. Inhibiting ABHD17 increased the plasma membrane localization of wild-type NOD2 and a subset of poorly acylated Crohn's disease-associated variants. This enhanced NOD2 activity, increasing NF-κB activation and pro-inflammatory cytokine production in epithelial cells.
CONCLUSIONS: These findings demonstrate that ABHD17 isoforms are negative regulators of NOD2. The results also suggest that targeting ABHD17 isoforms could restore functionality to specific Crohn's disease-associated NOD2 variants, offering a potential therapeutic strategy.

Keywords:  ABHD17; Acyl Protein Thioesterase; Crohn’s disease; IL-8; Inflammation; NOD2; S-acylation

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101491
Clin Rev Allergy Immunol. 2025 Mar 13. 68(1): 28

The Role of Lactate and Lactylation in the Dysregulation of Immune Responses in Psoriasis.

Xinxin Wu, Changya Liu, Caiyun Zhang, Le Kuai, Sheng Hu, Ning Jia, Jiankun Song, Wencheng Jiang, Qilong Chen, Bin Li.

  Historically, lactate has been considered merely a metabolic byproduct. However, recent studies have revealed that lactate plays a much more dynamic role, acting as an immune signaling molecule that influences cellular communication, through the process of "lactate shuttling." Lactylation, a novel post-translational modification, is directly derived from lactate and represents an emerging mechanism through which lactate exerts its effects on cellular function. It has been shown to directly affect immune cells by modulating the activation of pro-inflammatory and anti-inflammatory pathways. This modification influences the expression of key immune-related genes, thereby impacting immune cell differentiation, cytokine production, and overall immune response. In this review, we focused on the role of lactate and lactylation in the dysregulation of immune responses in psoriasis and its relapse. Additionally, we discuss the potential applications of targeting lactate metabolism and lactylation modifications in the treatment of psoriasis, alongside the investigation of artificial intelligence applications in advancing lactate and lactylation-focused drug development, identifying therapeutic targets, and enabling personalized medical decision-making. The significance of this review lies in its comprehensive exploration of how lactate and lactylation contribute to immune dysregulation, offering a novel perspective for understanding the metabolic and epigenetic changes associated with psoriasis. By identifying the roles of these pathways in modulating immune responses, this review provides a foundation for the development of new therapeutic strategies that target these mechanisms.

Keywords:  Lactate; Lactylation; Psoriasis

DOI:  https://doi.org/10.1007/s12016-025-09037-2
bioRxiv. 2025 Feb 27. pii: 2025.02.27.640596. [Epub ahead of print]

Evidence for Functional Regulation of the KLHL3/WNK Pathway by O-GlcNAcylation.

Jimin Hu, Duc T Huynh, Denise E Dunn, Jianli Wu, Cindy Manriquez-Rodriguez, Qianyi E Zhang, Gabrielle A Hirschkorn, George R Georgiou, Tetsuya Hirata, Samuel A Myers, Scott R Floyd, Jen-Tsan Chi, Michael Boyce.

The 42-member Kelch-like (KLHL) protein family are adaptors for ubiquitin E3 ligase complexes, governing the stability of a wide range of substrates. KLHL proteins are critical for maintaining proteostasis in a variety of tissues and are mutated in human diseases, including cancer, neurodegeneration, and familial hyperkalemic hypertension. However, the regulation of KLHL proteins remains incompletely understood. Previously, we reported that two KLHL family members, KEAP1 and gigaxonin, are regulated by O-linked β- N -acetylglucosamine (O-GlcNAc), an intracellular form of glycosylation. Interestingly, some ubiquitination targets of KEAP1 and gigaxonin are themselves also O-GlcNAcylated, suggesting that multi-level control by this post-translational modification may influence many KLHL pathways. To test this hypothesis, we examined KLHL3, which ubiquitinates with-no-lysine (WNK) kinases to modulate downstream ion channel activity. Our biochemical and glycoproteomic data demonstrate that human KLHL3 and all four WNK kinases (WNK1-4) are O-GlcNAcylated. Moreover, our results suggest that O-GlcNAcylation affects WNK4 function in both osmolarity control and ferroptosis, with potential implications ranging from blood pressure regulation to neuronal health and survival. This work demonstrates the functional regulation of the KLHL3/WNK axis by O-GlcNAcylation and supports a broader model of O-GlcNAc serving as a general regulator of KLHL signaling and proteostasis.

DOI: https://doi.org/10.1101/2025.02.27.640596
Immunity. 2025 Mar 11. pii: S1074-7613(25)00075-5. [Epub ahead of print]58(3): 535-554

Lactate: A key regulator of the immune response.

Alba Llibre, Salih Kucuk, Atrayee Gope, Michelangelo Certo, Claudio Mauro.

  Lactate, the end product of both anaerobic and aerobic glycolysis in proliferating and growing cells-with the latter process known as the Warburg effect-is historically considered a mere waste product of cell and tissue metabolism. However, research over the past ten years has unveiled multifaceted functions of lactate that critically shape and impact cellular biology. Beyond serving as a fuel source, lactate is now known to influence gene expression through histone modification and to function as a signaling molecule that impacts a wide range of cellular activities. These properties have been particularly studied in the context of both adaptive and innate immune responses. Here, we review the diverse roles of lactate in the regulation of the immune system during homeostasis and disease pathogenesis (including cancer, infection, cardiovascular diseases, and autoimmunity). Furthermore, we describe recently proposed therapeutic interventions for manipulating lactate metabolism in human diseases.

Keywords:  immune regulation; lactate; lactate sensing; lactate signaling; lactylation

DOI:  https://doi.org/10.1016/j.immuni.2025.02.008
J Proteomics. 2025 Mar 06. pii: S1874-3919(25)00046-6. [Epub ahead of print]316 105419

Characterization of substrate distribution and functional implication of lysine acylations in Staphylococcus aureus.

Yunxu Bian, Zunli Hu, Rongzhen Wang, Shuyu Xie, Yewen Sun, Tianqi Liu, Shaojie Ma, Bin Liu, Minjia Tan, Jun-Yu Xu.

  Staphylococcus aureus (S. aureus) is a major pathogen whose post-translational modifications (PTMs) regulate key biological processes that exert a substantial impact on protein function within this pathogen. In this study, we comprehensively analyzed the overall patterns of three lysine acylation in S. aureus including acetylation, succinylation, and malonylation. Using mass spectrometry, we identified 1249 acetylated, 871 succinylated, and 67 malonylated sites. Bioinformatic analysis furtherly revealed that both lysine acetylation and succinylation exhibited a preferential association with glutamate residues near the modified lysine positions. Pathway enrichment showed that modified substrates were associated with ribosomes and metabolic functions. Additional functional exploration showed that lysine succinylation significantly regulates the enzymatic activity of Glutamyl-tRNA amidotransferase and Carbamoyl phosphate synthase. In conclusion, our study enhanced the comprehension of lysine succinylation in S. aureus and highlights potential targets related to its pathogenicity at the post-translational modification level. SIGNIFICANCE NEW: Lysine acylations play important roles in regulating bacterial survival and pathogenicity in Staphylococcus aureus. However, comprehensive and systematic investigations of the lysine acylomes in S. aureus remain insufficient. In this study, we conducted a comprehensive analysis of three lysine acylation modifications in Staphylococcus aureus subspecies aureus ATCC 25923 using mass spectrometry-based proteomic techniques. The objective was to investigate the potential impact of these modifications on protein function. Our bioinformatics analysis identified a significant correlation between lysine acylations and both ribosomal and metabolic pathways. Through additional experimental validation, we have substantiated that lysine succinylation plays a significant regulatory role in the activities of Glutamyl-tRNA amidinotransferase and Carbamoyl phosphate synthetase, consequently exerting a profound impact on cellular energy metabolism and protein synthesis in S. aureus. Collectively, our study underscores the pivotal role of lysine acylation modifications in S. aureus in modulating enzyme function, thereby offering valuable insights into the biology of S. aureus and informing potential therapeutic strategies.

Keywords:  Acetylation; Malonylation; Post-translational modifications; Staphylococcus aureus; Succinylation

DOI:  https://doi.org/10.1016/j.jprot.2025.105419
Trends Cancer. 2025 Mar 06. pii: S2405-8033(25)00014-7. [Epub ahead of print]

Acetylation: a new target for protein degradation in cancer.

Callie E W Crawford, George M Burslem.

  Acetylation is an increasing area of focus for cancer research as it is closely related to a variety of cellular processes through modulation of histone and non-histone proteins. However, broadly targeting acetylation threatens to yield nonselective toxic effects owing to the vital role of acetylation in cellular function. There is thus a pressing need to elucidate and characterize the specific cancer-relevant roles of acetylation for future therapeutic design. Acetylation-mediated protein homeostasis is an example of selective acetylation that affects a myriad of proteins as well as their correlated functions. We review recent examples of acetylation-mediated protein homeostasis that have emerged as key contributors to tumorigenesis, tumor proliferation, metastasis, and/or drug resistance, and we discuss their implications for future exploration of this intriguing phenomenon.

Keywords:  acetylation; cancer; degradation; heterobifunctional; ubiquitination

DOI:  https://doi.org/10.1016/j.trecan.2025.01.013
Cell Commun Signal. 2025 Mar 12. 23(1): 134

L- and D-Lactate: unveiling their hidden functions in disease and health.

Jianting Li, Peng Ma, Zhizhen Liu, Jun Xie.

  Lactate, once considered a mere byproduct of anaerobic metabolism, is now recognized as a critical signaling molecule with diverse roles in physiology and pathology. There are two stereoisomers of lactate: L- and D-lactate. Recent studies have shown that disruptions in these two lactate stereoisomers have distinct effects on health and disease. L-lactate is central to glycolysis and energy transfer through the Cori cycle but also acts as the dominant lactylation isomer induced by glycolysis, influencing metabolism and cell survival. Although less studied, D-lactate is linked to metabolic disorders and plays a role in mitochondrial dysfunction and oxidative stress. This review focuses on both L- and D-lactate and examines their biosynthesis, transport, and expanding roles in physiological and pathological processes, particularly their functions in cancer, immune regulation, inflammation, neurodegeneration and other diseases. Finally, we assess the therapeutic prospects of targeting lactate metabolism, highlighting emerging strategies for intervention in clinical settings. Our review synthesizes the current understanding of L- and D-lactate, offering insights into their potential as targets for therapeutic innovation.

Keywords:  D-lactate; Epigenetic; L-lactate; Lactylation; Metabolism

DOI:  https://doi.org/10.1186/s12964-025-02132-z
Cell Death Discov. 2025 Mar 13. 11(1): 100

Lactylation: a promising therapeutic target in ischemia-reperfusion injury management.

Fei-Xiang Wang, Guo Mu, Zi-Hang Yu, Zu-An Shi, Xue-Xin Li, Xin Fan, Ye Chen, Jun Zhou.

Ischemia-reperfusion injury (IRI) is a critical condition that poses a significant threat to patient safety. The production of lactate increases during the process of IRI, and lactate serves as a crucial indicator for assessing the severity of such injury. Lactylation, a newly discovered post-translational modification in 2019, is induced by lactic acid and predominantly occurs on lysine residues of histone or nonhistone proteins. Extensive studies have demonstrated the pivotal role of lactylation in the pathogenesis and progression of various diseases, including melanoma, myocardial infarction, hepatocellular carcinoma, Alzheimer's disease, and nonalcoholic fatty liver disease. Additionally, a marked correlation between lactylation and inflammation has been observed. This article provides a comprehensive review of the mechanism underlying lactylation in IRI to establish a theoretical foundation for better understanding the interplay between lactylation and IRI.

DOI: https://doi.org/10.1038/s41420-025-02381-4
Life Sci. 2025 Mar 07. pii: S0024-3205(25)00181-X. [Epub ahead of print]369 123547

Regulation of autophagy: Insights into O-GlcNAc modification mechanisms.

Chengzhi Liu, Xinyu Wang, Shengnan Xu, Mingyue Liu, Xusheng Cao.

  Autophagy is a "self-eating" biological process that degrades cytoplasmic contents to ensure cellular homeostasis. Its response to stimuli occurs in two stages: Within a few to several hours of exposure to a stress condition, autophagic flow rapidly increases, which is mediated by post-translational modification (PTM). Subsequently, the transcriptional program is activated and mediates the persistent autophagic response. O-linked β-N-acetylglucosamine (O-GlcNAc) modification is an inducible and dynamically cycling PTM; mounting evidence suggests that O-GlcNAc modification participates in the total autophagic process, including autophagy initiation, autophagosome formation, autophagosome-lysosome fusion, and transcriptional process. In this review, we summarize the current knowledge on the emerging role of O-GlcNAc modification in regulating autophagy-associated proteins and explain the different regulatory effects on autophagy exerted by O-GlcNAc modification.

Keywords:  Autophagy; O-linked β-N-acetylglucosamine modification; Post-translational modification; Regulation; Selective autophagy

DOI:  https://doi.org/10.1016/j.lfs.2025.123547
Metabolism. 2025 Mar 11. pii: S0026-0495(25)00055-1. [Epub ahead of print] 156186

Pharmacologically targeting fatty acid synthase-mediated de novo lipogenesis alleviates osteolytic bone loss by directly inhibiting osteoclastogenesis through suppression of STAT3 palmitoylation and ROS signaling.

Chunmei Xiu, Lei Zhang, Chenxi Zhang, Yuannan Zhang, Xi Luo, Ziyi Zhang, Hangkai Zhao, Kaizhong Ji, Zhiyuan Chen, Guangxu He, Jianquan Chen.

  Aberrant increases in osteoclast formation and/or activity are the underlying cause of bone loss in a variety of osteolytic diseases. Fatty acid synthase (Fasn)-mediated de novo lipogenesis (DNL) is one of the major lipid metabolic pathways and has been shown to play critical roles in diverse physiological and pathological processes. However, little is known about its role in osteoclastogenesis. Here, we investigate the direct role of DNL in osteoclastogenesis and its therapeutic potential in osteolytic diseases. We found that Fasn expression and DNL levels are upregulated during receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Inhibition of Fasn by shRNA knockdown or its pharmacological inhibitors (ASC40 and trans-C75) impairs osteoclast differentiation in vitro. Mechanistically, pharmacological inhibition of Fasn suppresses RANKL-induced c-Fos/NFATc1 expression and thus osteoclastogenesis partly by disrupting STAT3 palmitoylation, while promoting ROS scavenging to impair mitogen-activated protein kinase (MAPK) signaling. Finally, the therapeutic potential of ASC40 for the treatment of osteolytic bone loss is tested in two mouse models of osteolytic diseases, i.e. ovariectomy (OVX)-induced osteoporosis and titanium nanoparticle-induced calvarial osteolysis. The results show that ASC40 significantly attenuates bone loss and osteoclastogenesis in both models. In conclusion, our results demonstrate that Fasn-mediated DNL is a novel positive regulator of osteoclastogenesis and may serve as a promising therapeutic target for the treatment of osteoclast-driven osteolytic bone diseases.

Keywords:  ASC40; Fatty acid synthase; Osteoclastogenesis; Protein S-palmitoylation; Reactive oxygen species; STAT3

DOI:  https://doi.org/10.1016/j.metabol.2025.156186
Eur J Immunol. 2025 Mar;55(3): e202451318

Tumor Glycosylation: A Main Player in the Modulation of Immune Responses.

Ernesto Rodriguez.

  Tumor immune escape refers to the process by which cancer cells evade detection and destruction by the immune system. Glycosylation, a post-translational modification that is altered in almost all cancer types, plays a crucial role in this process by modulating immune responses. This review examines our current understanding of how aberrant tumor glycosylation contributes to a tolerogenic microenvironment, focusing on specific glycosylation signatures-fucosylation, truncated O-glycans, and sialylation-and the immune receptors involved. Additionally, the clinical significance of tumor glycosylation is discussed, emphasizing its potential in developing novel therapeutic approaches aimed at improving immune system recognition and targeting of cancer cells. The review underscores the importance of ongoing research in this area to identify effective strategies for countering tumor immune escape and enhancing the efficacy of cancer treatments.

Keywords:  cancer; glycosylation; glyco‐code; lectin receptors

DOI:  https://doi.org/10.1002/eji.202451318
Isr J Chem. 2024 Dec;pii: e202300162. [Epub ahead of print]64(12):

Protein Glycosylation Patterns Shaped By the IRE1-XBP1s Arm of the Unfolded Protein Response.

Kenny Chen, Matthew D Shoulders.

  The unfolded protein response (UPR) is a sensing and signaling pathway that surveys the endoplasmic reticulum (ER) for protein folding challenges and responds whenever issues are detected. UPR activation leads to upregulation of secretory pathway chaperones and quality control factors, as well as reduces the nascent protein load on the ER, thereby restoring and maintaining proteostasis. This paradigm-defining view of the role of the UPR is accurate, but it elides additional key functions of the UPR in cell biology. In particular, recent work has revealed that the UPR can shape the structure and function of N- and O-glycans installed on ER client proteins. This crosstalk between the UPR's response to protein misfolding and the regulation of glycosylation remains insufficiently understood. Still, emerging evidence makes it clear that the UPR, and particularly the IRE1-XBP1s arm of the UPR, may be a central regulator of protein glycosylation with important biological consequences. In this review, we discuss the crosstalk between proteostasis, the UPR, and glycosylation, present progress towards understanding biological functions of this crosstalk, and examine potential roles in diseases such as cancer.

Keywords:  Endoplasmic reticulum stress; N-Glycosylation; O-Glycosylation; Protein folding; Proteostasis

DOI:  https://doi.org/10.1002/ijch.202300162
J Biochem Mol Toxicol. 2025 Mar;39(3): e70227

N-Acetyltransferase 10 Promotes Gastric Cancer Progression by Mediating the N4-Acetylcytidine Modification of Lactate Dehydrogenase A.

Juan Liang, Peng Zhai, Guohua Cheng, Jinlong Han, Xiang Song.

  The N4-acetylcytidine (ac4C) modification, which is catalyzed by NAT10, represents a significant posttranscriptional modification of mRNA in multiple cancers. However, the significance of this modification in gastric cancer (GC) progression remains unclear. To evaluate the potential of differential NAT10 expression in GC, RT-qPCR and western blot were employed. Dot blot and acRIP were utilized for total ac4C and LDHA mRNA ac4C detection. Subsequently, the effects of NAT10 on GC cell viability and glycolysis were assessed by Cell Counting Kit-8 and glycolysis-related indicator detection Kits. Furthermore, rescue experiments and mice xenograft experiments were conducted to investigate the mechanism underlying the NAT10/LDHA signaling axis in GC. This study identified upregulated NAT10 and ac4C levels in GC. Knockdown of NAT10 led to inhibited cell viability and glycolysis. Additionally, NAT10 directly bound to LDHA mRNA. NAT10 silencing decreased the expression and stability of LDHA mRNA, as well as its ac4C modification level. Interestingly, LDHA overexpression partially reversed the effects of NAT10 knockdown on cell viability and glycolysis. Eventually, the oncogenic effect of NAT10/ac4C/LDHA axis was confirmed in xenograft experiments. NAT10 promoted the GC progression by mediating the ac4C modification of LDHA mRNA, which could serve as a potential therapeutic target for GC.

Keywords:  LDHA; NAT10; gastric cancer; glycolysis

DOI:  https://doi.org/10.1002/jbt.70227
bioRxiv. 2025 Feb 28. pii: 2025.02.25.640220. [Epub ahead of print]

Class I histone deacetylases catalyze lysine lactylation.

Takeshi Tsusaka, Mohd Altaf Najar, Isha Sharma, Mariola M Marcinkiewicz, Claudia Veronica Da Silva Crispim, Nathaniel W Snyder, George M Burslem, Emily L Goldberg.

Metabolism and post-translational modifications (PTMs) are intrinsically linked and the number of identified metabolites that can covalently modify proteins continues to increase. This metabolism/PTM crosstalk is especially true for lactate, the product of anaerobic metabolism following glycolysis. Lactate forms an amide bond with the ε-amino group of lysine, a modification known as lysine lactylation, or Kla. Multiple independent mechanisms have been proposed in the formation of Kla, including p300/CBP-dependent transfer from lactyl-CoA, via a high-energy intermediate lactoylglutathione species that non-enzymatically lactylates proteins, and several enzymes are reported to have lactyl transferase capability. We recently discovered that class I histone deacetylases (HDACs) 1, 2, and 3 can all reverse their canonical chemical reaction to catalyze lysine β-hydroxybutyrylation. Here we tested the hypothesis that HDACs can also catalyze Kla formation. Using biochemical, pharmacological, and genetic approaches, we found that HDAC-catalyzed lysine lactylation accounts for the majority of Kla formation in cells. Dialysis experiments confirm this is a reversible reaction that depends on lactate concentration. We also directly quantified intracellular lactyl-CoA and found that Kla abundance can be uncoupled from lactyl-CoA levels. Therefore, we propose a model in which the majority of Kla is formed through enzymatic addition of lactate by HDACs 1, 2, and 3.

DOI: https://doi.org/10.1101/2025.02.25.640220