bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–04–20
eleven papers selected by
Bruna Martins Garcia, CABIMER
  1. The mechanisms and effects of lactylation modification in different kinds of cancers.
  2. Lactylation in Glioblastoma: A Novel Epigenetic Modifier Bridging Epigenetic Plasticity and Metabolic Reprogramming.
  3. Engineered depalmitoylases enable selective manipulation of protein localization and function.
  4. Protocol to study the genomic profile of histone lactylation with CUT&RUN assay in tumor-associated macrophages.
  5. Detection and Analysis of S-Acylated Proteins via Acyl Resin-Assisted Capture (Acyl-RAC).
  6. KAT3B Promotes the Glycolysis and Malignant Progression of Lung Cancer by Mediating the Succinylation Modification of PKM2.
  7. SIRT5 Alleviates Apoptosis of Vascular Endothelial Cells Under Simulated Microgravity via Desuccinylation of ERO1A.
  8. Palmitoylation in cardiovascular diseases: Molecular mechanism and therapeutic potential.
  9. The glycosyltransferase ALG3 is an AKT substrate that regulates protein N-glycosylation.
  10. Astragaloside IV-PESV facilitates pyroptosis by enhancing palmitoylation of GSDMD protein mediated by ZDHHC1.
  11. Glutamylation of centrosomes ensures their function by recruiting microtubule nucleation factors.
  1. Discov Oncol. 2025 Apr 18. 16(1): 560
    The mechanisms and effects of lactylation modification in different kinds of cancers.
    Yixun Sun, Xiaxia Yang, Feifei Kong, Feng Yun Dong, Na Li, Sen Wang.
      Lactylation, a recently identified post-translational modification, has garnered significant attention for its associations with various diseases, particularly its critical role in tumor progression and treatment. It is emerging as a potential clinical target. The elevated metabolic activity of cancer cells often leads to excessive lactate accumulation, a phenomenon termed the "Warburg effect", which is a hallmark of the tumor microenvironment. Recent research reveals that lactate is not merely a metabolic byproduct but also serves as a substrate for protein lactylation, influencing tumor development by regulating cellular signaling, gene expression, and immune responses. This dual role has become a focal point for scientists and clinicians seeking novel therapeutic strategies targeting lactate-related pathways. Despite growing interest, the detailed mechanisms and therapeutic applications of lactylation across different cancer types remain inadequately explored. This review synthesizes current findings on lactylation mechanisms in various tumors, highlights potential therapeutic targets, and offers new perspectives to advance cancer treatment.
    Keywords:  Cancer; Clinical applications; Lactylation modification; Modified transferases; Warburg effect
    DOI:  https://doi.org/10.1007/s12672-025-02359-9
  2. Int J Mol Sci. 2025 Apr 04. pii: 3368. [Epub ahead of print]26(7):
    Lactylation in Glioblastoma: A Novel Epigenetic Modifier Bridging Epigenetic Plasticity and Metabolic Reprogramming.
    Qingya Qiu, Hui Deng, Ping Song, Yushu Liu, Mengxian Zhang.
      Glioblastoma, the most common and aggressive primary malignant brain tumor, is characterized by a high rate of recurrence, disability, and lethality. Therefore, there is a pressing need to develop more effective prognostic biomarkers and treatment approaches for glioblastoma. Lactylation, an emerging form of protein post-translational modification, has been closely associated with lactate, a metabolite of glycolysis. Since the initial identification of lactylation sites in core histones in 2019, accumulating evidence has shown the critical role that lactylation plays in glioblastoma development, assessment of poor clinical prognosis, and immunosuppression, which provides a fresh angle for investigating the connection between metabolic reprogramming and epigenetic plasticity in glioblastoma cells. The objective of this paper is to present an overview of the metabolic and epigenetic roles of lactylation in the expanding field of glioblastoma research and explore the practical value of developing novel treatment plans combining targeted therapy and immunotherapy.
    Keywords:  epigenetic remodeling; glioblastoma; lactylation; metabolic reprogramming
    DOI:  https://doi.org/10.3390/ijms26073368
  3. Nat Commun. 2025 Apr 13. 16(1): 3514
    Engineered depalmitoylases enable selective manipulation of protein localization and function.
    Srinidhi Jayaraman, Audrey Kochiss, Thy-Lan Alcalay, Pedro J Del Rivero Morfin, Manu Ben-Johny.
      S-Palmitoylation is a reversible post-translational modification that tunes the localization, stability, and function of an impressive array of proteins including ion channels, G-proteins, and synaptic proteins. Indeed, altered protein palmitoylation is linked to various human diseases including cancers, neurodevelopmental and neurodegenerative diseases. As such, strategies to selectively manipulate protein palmitoylation with enhanced temporal and subcellular precision are sought after to both delineate physiological functions and as potential therapeutics. Here, we develop chemogenetically and optogenetically inducible engineered depalmitoylases to manipulate the palmitoylation status of target proteins. We demonstrate that this strategy is programmable allowing selective depalmitoylation in specific organelles, triggered by cell-signaling events, and of individual protein complexes. Application of this methodology revealed bidirectional tuning of neuronal excitability by distinct depalmitoylases. Overall, this strategy represents a versatile and powerful method for manipulating protein palmitoylation in live cells, providing insights into their regulation in distinct physiological contexts.
    DOI:  https://doi.org/10.1038/s41467-025-58908-x
  4. STAR Protoc. 2025 Apr 11. pii: S2666-1667(25)00172-8. [Epub ahead of print]6(2): 103766
    Protocol to study the genomic profile of histone lactylation with CUT&RUN assay in tumor-associated macrophages.
    Alessandra De Leo, Alessio Ugolini, Filippo Veglia.
      Lysine lactylation is a distinctive histone modification that plays a crucial role in epigenetic regulation and gene transcription. Here, we present a protocol for studying the genomic profile of histone lactylation with the CUT&RUN assay in tumor-associated macrophages. We describe steps for preparing live cells, gating strategies for isolating glucose transporter type 1 + (GLUT1+) monocyte-derived macrophages (MDMs) by fluorescence-activated cell sorting (FACS), binding lactyl-specific primary antibodies, and quantifying DNA using qPCR. This protocol is applicable to both tumor-derived and in-vitro-generated bone-marrow-derived macrophages. For complete details on the use and execution of this protocol, please refer to De Leo et al.1.
    Keywords:  Genomics; Immunology; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2025.103766
  5. Bio Protoc. 2025 Apr 05. 15(7): e5268
    Detection and Analysis of S-Acylated Proteins via Acyl Resin-Assisted Capture (Acyl-RAC).
    Dina A Abdulrahman, Michael Veit.
      Protein palmitoylation is a lipid modification where a palmitoyl group is covalently attached via a thioester linkage to one or more cysteines on a substrate protein. This modification, catalyzed by a group of enzymes named DHHC enzymes after their conserved Asp-His-His-Cys motif, plays a significant role in regulating the localization, stability, and function of a wide range of cellular and viral proteins. By influencing how and where proteins interact within the cell, palmitoylation is essential for various cellular processes, including signaling pathways, membrane dynamics, and protein-protein interactions. Here, we describe the acyl-RAC assay, a biochemical technique designed to specifically enrich and analyze palmitoylated proteins from complex biological samples, such as cell lysates or tissue extracts. The assay begins by reducing and blocking free cysteine thiol groups on proteins, ensuring that only those thiols involved in thioester bonds with palmitates are accessible for downstream analysis. These thioester bonds are then cleaved to release the fatty acids from the cysteines, which are subsequently captured using thiopropyl Sepharose beads that bind to the newly exposed thiol groups. The captured proteins are eluted from the beads by breaking the bond between the thiol and the resin with reducing agents, and the proteins are then analyzed by SDS-PAGE followed by western blotting to identify and quantify them. The acyl-RAC assay's specificity for S-palmitoylated proteins makes it an invaluable tool for exploring this modification. It not only allows for the identification of previously unknown palmitoylated proteins, thereby deepening our understanding of palmitoylation in cellular processes and viral infections, but it also enables quantitative comparisons of protein palmitoylation under different experimental conditions or treatments. Key features • Allows identification of acylated proteins. • Quantitative analysis of S-palmitoylation levels under various conditions by western blot. • Requires at least seven days to complete.
    Keywords:  Lipid modification; S-palmitoylation; SARS-CoV-2; SDS-PAGE; Spike protein; Thiol-specific chemistry; Western blotting
    DOI:  https://doi.org/10.21769/BioProtoc.5268
  6. J Biochem Mol Toxicol. 2025 Apr;39(4): e70259
    KAT3B Promotes the Glycolysis and Malignant Progression of Lung Cancer by Mediating the Succinylation Modification of PKM2.
    Zhifeng Guo, Yan Hui, Siqi Sun, Fanlong Kong.
      Lysine succinyltransferase KAT3B plays a critical role in the progression of various cancers by modulating key metabolic pathways, including glycolysis. However, the function and underlying mechanism of KAT3B in glycolysis and lung cancer (LC) progression remain to be further studied. We determined mRNA expression levels of lysine succinyl-modifying enzymes through qRT-PCR. Protein expression and succinylation status of glycolysis-related proteins PKM2, LDHA, and ENO1 were analyzed via Western blot. Co-immunoprecipitation and immunofluorescence microscopy were employed to verify the interaction between KAT3B and PKM2. Bioinformatics analysis predicted succinylation sites on PKM2, which were subsequently validated through site-directed mutagenesis. The effects of KAT3B and PKM2 on LC cell malignancy and glycolysis were evaluated using CCK-8, transwell migration, glucose uptake, lactate production, ECAR, and OCR assays. A xenograft tumor model was utilized to assess the impact of KAT3B on LC tumor growth. We confirmed the augmentation of KAT3B in LC, which also was correlated with advanced TNM stages and elevated T stages of LC patients. Conversely, KAT3B knockdown suppressed the growth, metastasis, and glycolytic activity of LC cells in vitro, while also inhibiting tumor growth in vivo. KAT3B mediated succinylation at PKM2 K298, and the suppression of LC cell malignancy and glycolysis upon KAT3B downregulation was largely reversed by upregulation of PKM2. The KAT3B/PKM2 axis may be a novel target for LC therapy.
    Keywords:  KAT3B; PKM2; glycolysis; lung cancer; succinylation modification
    DOI:  https://doi.org/10.1002/jbt.70259
  7. Int J Mol Sci. 2025 Mar 23. pii: 2908. [Epub ahead of print]26(7):
    SIRT5 Alleviates Apoptosis of Vascular Endothelial Cells Under Simulated Microgravity via Desuccinylation of ERO1A.
    Yikai Pan, Qian Zhang, Chengfei Li, Xi Li, Shuhan Li, Yuan Wang, Ruonan Wang, Jieyi Fan, Yateng Tie, Xingcheng Zhao, Yuan Gao, Yongchun Wang, Xiqing Sun.
      The adverse effects of weightlessness on the human cardiovascular system greatly hinder the process of long-term and long-distance space exploration. Succinylation is an important type of protein post-translational modification. However, whether succinylation modification is able to play a role in altered vascular endothelial cell function under microgravity or simulated microgravity has not been reported. This study aims to investigate the quantitative global proteome and the changes in lysine succinylation in related proteins, seeking to facilitate a better understanding of the protein post-translational modification in cardiovascular deconditioning under microgravity. LC-MS/MS combined with bioinformatics analysis were used to quantitatively detect the perspectives at the global protein level. Immunoprecipitation and Western blot analysis were conducted to further verify the alterations of related proteins and lysine succinylation. A total of 132 differentially expressed proteins and 164 differentially expressed lysine succinylation sites were identified in human umbilical vein endothelial cells (HUVECs). Bioinformatics analysis indicates that lysine succinylation may play a potential role in energy metabolism. In addition, desuccinylase SIRT5 was downregulated and regulated succinylation modification levels of HUVECs under simulated microgravity. Notably, the overexpression of SIRT5 effectively protected HUVECs from apoptosis induced by simulated microgravity. And the succinylation of Lys396 in ERO1A was significantly increased in HUVECs under simulated microgravity. Mechanistically, the knockdown of SIRT5 was found to induce the apoptosis of HUVECs through the succinylation of Lys396 in ERO1A. These results can provide new ideas for elucidating the molecular mechanism of cardiovascular dysfunction in microgravity environments, and provide key molecular targets for scientific protective measures against microgravity in space.
    Keywords:  ERO1A; SIRT5; apoptosis; microgravity; succinylation; vascular endothelial cells
    DOI:  https://doi.org/10.3390/ijms26072908
  8. Int J Cardiol Heart Vasc. 2025 Jun;58 101675
    Palmitoylation in cardiovascular diseases: Molecular mechanism and therapeutic potential.
    Rongli Wang, Yi He, Yan Wang, Jing Wang, Hu Ding.
      Cardiovascular disease is one of the leading causes of mortality worldwide, and involves complex pathophysiological mechanisms that encompass various biological processes and molecular pathways. Post-translational modifications of proteins play crucial roles in the occurrence and progression of cardiovascular diseases, among which palmitoylation is particularly important. Various proteins associated with cardiovascular diseases can be palmitoylated to enhance the hydrophobicity of their molecular subdomains. This lipidation can significantly affect some pathophysiological processes, such as metabolism, inflammation by altering protein stability, localization, and signal transduction. In this review, we narratively summarize recent advances in the palmitoylation of proteins related to cardiovascular diseases and discuss its potential as a therapeutic target.
    Keywords:  Cardiovascular diseases; Palmitoylation; Post-translational modifications; zDHHC
    DOI:  https://doi.org/10.1016/j.ijcha.2025.101675
  9. bioRxiv. 2025 Apr 03. pii: 2025.04.01.646556. [Epub ahead of print]
    The glycosyltransferase ALG3 is an AKT substrate that regulates protein N-glycosylation.
    Adrija J Navarro-Traxler, Laura Ghisolfi, Evan C Lien, Alex Toker.
      The PI3K/AKT signaling pathway is frequently dysregulated in cancer and controls key cellular processes such as survival, proliferation, metabolism and growth. Protein glycosylation is essential for proper protein folding and is also often deregulated in cancer. Cancer cells depend on increased protein folding to sustain oncogene-driven proliferation rates. The N-glycosyltransferase asparagine-linked glycosylation 3 homolog (ALG3), a rate-limiting enzyme during glycan biosynthesis, catalyzes the addition of the first mannose to glycans in an alpha-1,3 linkage. Here we show that ALG3 is phosphorylated downstream of the PI3K/AKT pathway in both growth factor-stimulated cells and PI3K/AKT hyperactive cancer cells. AKT directly phosphorylates ALG3 in the amino terminal region at Ser11/Ser13. CRISPR/Cas9-mediated depletion of ALG3 leads to improper glycan formation and induction of endoplasmic reticulum stress, the unfolded protein response, and impaired cell proliferation. Phosphorylation of ALG3 at Ser11/Ser13 is required for glycosylation of cell surface receptors EGFR, HER3 and E-cadherin. These findings provide a direct link between PI3K/AKT signaling and protein glycosylation in cancer cells.
    DOI:  https://doi.org/10.1101/2025.04.01.646556
  10. Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr 16.
    Astragaloside IV-PESV facilitates pyroptosis by enhancing palmitoylation of GSDMD protein mediated by ZDHHC1.
    Xujun You, Honghan Li, Qixin Li, Qing Zhang, Yiguo Cao, Wei Fu, Bin Wang.
      Prostate cancer (PCa) is an epithelial malignancy affecting the prostate gland. Astragaloside IV combined with polypeptide extract from scorpion venom (PESV) has been reported to inhibit the growth of PCa. This study aimed to investigate the mechanisms by which this combination mitigates the progression of PCa. Bioinformatic analysis was utilized to investigate the correlation between zinc finger DHHC-type containing 1 (ZDHHC1) expression and PCa progression. The extent of pyroptosis in PCa cells was assessed by measuring cell viability, IL-1β and IL-18 secretion, LDH release, and HMGB1 content. PCa mouse models were constructed by subcutaneous injection of DU145 or PC-3 cells into nude mice, with subsequent monitoring of tumor weight and volume. ZDHHC1 expression was significantly lower in PCa patient tissues, which correlated with a poor prognosis. ZDHHC1 overexpression inhibited PC-3 and DU145 cell viability and increased IL-1β, IL-18, LDH, and HMGB1 levels in cell supernatants. Notably, the pyroptosis inhibitor LDC7559 partially reversed these effects. Co-IP assay demonstrated an interaction between ZDHHC1 and GSDMD. ZDHHC1 overexpression significantly enhanced GSDMD palmitoylation-mediated membrane translocation and pyroptosis; however, this effect was partially reversed by the palmitoylation inhibitor 2-BP. The combination of Astragaloside IV and PESV promoted GSDMD membrane translocation and pyroptosis in PCa cells, with ZDHHC1 knockdown partially reversing the effects of Astragaloside IV-PESV. Furthermore, treatment with Astragaloside IV-PESV significantly inhibited tumor tissue growth in tumor-bearing nude mouse models. Astragaloside IV-PESV enhances palmitoylation-mediated membrane translocation of GSDMD-N by upregulating ZDHHC1 expression, thereby facilitating pyroptosis in PCa cells and attenuating PCa progression.
    Keywords:  Astragaloside IV-PESV; GSDMD; Palmitoylation; Prostate cancer; ZDHHC1
    DOI:  https://doi.org/10.1007/s00210-025-04122-x
  11. EMBO J. 2025 Apr 14.
    Glutamylation of centrosomes ensures their function by recruiting microtubule nucleation factors.
    Shi-Rong Hong, Yi-Chien Chuang, Wen-Ting Yang, Chiou-Shian Song, Hung-Wei Yeh, Bing-Huan Wu, I-Hsuan Lin, Po-Chun Chou, Shiau-Chi Chen, Lohitaksh Sharma, Jui-Chen Lu, Rou-Ying Li, Ya-Chu Chang, Kuan-Ju Liao, Hui-Chun Cheng, Won-Jing Wang, Lily Hui-Ching Wang, Yu-Chun Lin.
      Centrosomes are tubulin-based organelles that undergo glutamylation, a post-translational modification that conjugates glutamic acid residues to tubulins. Although centrosomal glutamylation has been known for several decades, how this modification regulates centrosome structure and function remains unclear. To address this long-standing issue, we developed a method to spatiotemporally reduce centrosomal glutamylation by recruiting an engineered deglutamylase to centrosomes. We found that centrosome structure remains largely unaffected by centrosomal hypoglutamylation. Intriguingly, glutamylation physically recruits, via electrostatic forces, the NEDD1/CEP192/γ-tubulin complex to centrosomes, ensuring microtubule nucleation and proper trafficking of centriolar satellites. The consequent defect in centriolar satellite trafficking leads to reduced levels of the ciliogenesis factor Talpid3, suppressing ciliogenesis. Centrosome glutamylation also promotes proper mitotic spindle formation and mitosis. In summary, our study provides a new approach to spatiotemporally manipulate glutamylation at centrosomes, and offers novel insights into how centrosomes are organized and regulated by glutamylation.
    Keywords:  Centriolar satellites; Centrosomes; Glutamylation; Microtubules; Primary Cilia
    DOI:  https://doi.org/10.1038/s44318-025-00435-y
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒20 at 19:05.