bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–03–30
eighteen papers selected by
Bruna Martins Garcia, CABIMER



  1. Exp Mol Med. 2025 Mar 24.
      Increased glycolysis, which leads to high lactate production, is a common feature of cancer cells. Recent evidence suggests that lactate plays a role in the post-translational modification of histone and nonhistone proteins via lactylation. In contrast to genetic mutations, lactylation in cancer cells is reversible. Thus, reversing lactylation can be exploited as a pharmacological intervention for various cancers. Here we discuss recent advances in histone and nonhistone lactylation in cancer, including L-, D- and S-lactylation, as well as alanyl-tRNA synthetase as a novel lactyltransferase. We also discuss potential approaches for targeting lactylation as a therapeutic opportunity in cancer treatment.
    DOI:  https://doi.org/10.1038/s12276-025-01410-7
  2. Dev Dyn. 2025 Mar 28.
       BACKGROUND: Histone post-translational modification (PTM) is an important epigenomic regulation content and an essential process regulating gene expression. Histone lysine lactylation is the newly identified histone PTM that utilizes the lactyl moiety for its modification. Although histone lysine lactylation is considered an essential outcome of the Wardburg effects and the interconnection between cellular metabolism and gene regulation, the developmental contexts involving this PTM are largely unknown. In this study, we comprehensively observed histone lysine lactylation during Drosophila oogenesis, one of the developmental contexts in which chromatin regulation plays crucial roles.
    RESULTS: Our study revealed that lactylation on the specific histone lysine mainly occurs in the oocyte karyosome and condensed meiotic chromosome, suggesting histone lysine lactylation has a vital role in female meiosis. Interestingly, one of the histone lysine lactylations, lactylation of lysine 14 of histone H3, is intensively observed in the meiotic germline in the mouse ovary, suggesting that lactylation has an evolutionarily conserved role.
    CONCLUSIONS: Our results revealed that histone lysine lactylation is predominantly present in transcriptionally repressive meiotic chromatin, which contradicts the previously reported function of histone lactylation in transcriptional activation. This study, therefore, provides the first fundamental information to understand the role of histone lysine lactylation in the germline and repressive chromatin.
    Keywords:  gametogenesis; germline; histone‐lysine‐lactylation; meiosis
    DOI:  https://doi.org/10.1002/dvdy.70010
  3. Nat Chem Biol. 2025 Mar 26.
      The dynamic modification of proteins by many metabolites suggests an intimate link between energy metabolism and post-translational modifications (PTMs). For instance, starvation and low-carbohydrate diets lead to the accumulation of β-hydroxybutyrate (BHB), whose blood concentrations can reach millimolar levels, concomitant with the accumulation of lysine β-hydroxybutyrylation (Kbhb) of proteins. Here we report that class I histone deacetylases (HDACs) unexpectedly catalyze the formation of Kbhb. Through mutational analysis, we show a shared reliance on key active site amino acids for classical deacetylation and noncanonical HDAC-catalyzed β-hydroxybutyrylation. On the basis of these data, we propose that HDACs catalyze a condensation reaction between the free amine group on lysine and the BHB carboxylic acid, thereby generating an amide bond. This reversible HDAC activity is not limited to BHB and extends to multiple short-chain fatty acids, representing a novel mechanism of PTM deposition relevant to metabolically sensitive proteome modifications.
    DOI:  https://doi.org/10.1038/s41589-025-01869-5
  4. Genes (Basel). 2025 Mar 12. pii: 334. [Epub ahead of print]16(3):
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder with limited treatment options. This review explores the role of post-translational modifications (PTMs) in MASLD pathogenesis, highlighting their potential as therapeutic targets. We discuss the impact of PTMs, including their phosphorylation, ubiquitylation, acetylation, and glycosylation, on key proteins involved in MASLD, drawing on studies that use both human subjects and animal models. These modifications influence various cellular processes, such as lipid metabolism, inflammation, and fibrosis, contributing to disease progression. Understanding the intricate PTM network in MASLD offers the potential for developing novel therapeutic strategies that target specific PTMs to modulate protein function and alleviate disease pathology. Further research is needed to fully elucidate the complexity of PTMs in MASLD and translate these findings into effective clinical applications.
    Keywords:  MASH; MASLD; liver; post-translational modifications; proteomics
    DOI:  https://doi.org/10.3390/genes16030334
  5. Commun Biol. 2025 Mar 22. 8(1): 477
      The cluster of differentiation 38 (CD38) is a multifunctional transmembrane protein involved in numerous physiological and pathological processes including aging, neurodegenerative diseases, and tumorigenesis, hence is an attractive drug target. However, the mechanisms underlying the regulation of CD38 expression remain enigmatic. Herein, we report for the first time that CD38 is palmitoylated at Cys16, and that S-palmitoylation is required to maintain CD38 protein expression in tumor cells. Furthermore, we identify DHHC9 as the palmitoyl transferase and APT1 as the acylprotein thioesterase responsible for this crucial post-translational modification. Finally, we designed a competitive peptide of CD38 palmitoylation that decreases CD38 expression in tumor cells and suppresses tumor progression in vivo. These findings provide novel insight into CD38 regulation and highlight potential therapeutic strategies targeting CD38 palmitoylation for cancer treatment.
    DOI:  https://doi.org/10.1038/s42003-025-07897-0
  6. Adv Sci (Weinh). 2025 Mar 27. e2415530
      Lactylation is a novel post-translational modification mediated by lactate, widely present in the lysine residues of both histone and non-histone proteins. However, the specific regulatory mechanisms and downstream target proteins remain unclear. Herein, it is demonstrated that the RCC2 protein may serve as a critical link between material metabolism and cell division, promoting the rapid proliferation of breast cancer under high glucose conditions. Mechanistically, the activation of glycolysis leads to an increase in lactate. Then, acyltransferase KAT2A mediates RCC2 lactylation at K124, which assists RCC2 in recruiting free SERBP1, thereby stabilizing MAD2L1 mRNA. The lactylation of RCC2 mediates the activation of the cellular MAD2L1 signaling pathway and contributes to the progression of breast cancer. A small molecule inhibitor slows down cell proliferation by binding to the RCC2 active pocket and specifically blocking RCC2 lactylation. The findings elucidate the mechanism behind the upregulation of MAD2L1 in murine tumors associated with a high-sugar diet as reported in prior study and suggest a novel therapeutic strategy of targeting RCC2 lactylation to restrict the rapid proliferation of breast cancer cell in a high-lactate microenvironment.
    Keywords:  MAD2L1; RCC2; SERBP1; cell division; high sugar diet
    DOI:  https://doi.org/10.1002/advs.202415530
  7. Aging Dis. 2025 Mar 27.
      Cellular senescence is the basic unit of organismal aging, a complicated biological process involving several cell types and tissues. It is also an important mechanism by which the body responds to damage and potential carcinogenesis. However, excessive or abnormal cellular senescence can lead to tissue functional degradation and the occurrence of diseases. In recent years, the role of epigenetic modifications in cellular senescence has received extensive attention. Lactylation, a novel post-translational modification derived from lactate, has recently gained significant attention as a key factor in cellular metabolism and epigenetic regulation, gradually demonstrating its importance in the regulation of cellular senescence. This review emphasizes the bidirectional causal relationship between lactylation and cellular senescence, highlighting its potential as a therapeutic target for aging-related diseases.
    DOI:  https://doi.org/10.14336/AD.2025.0277
  8. Trends Biochem Sci. 2025 Mar 26. pii: S0968-0004(25)00049-0. [Epub ahead of print]
      Autophagy is an intracellular degradation system that delivers cytoplasmic materials to the lysosome. S-acylation, a reversible post-translational modification that attaches long-chain fatty acids to cysteine residues within proteins, has recently emerged as an important regulatory mechanism for autophagy. In this forum article, we review and discuss the emerging roles of S-acylation in autophagy.
    Keywords:  ATG proteins; S-acylation; autophagy; autophagy receptor
    DOI:  https://doi.org/10.1016/j.tibs.2025.02.007
  9. Brain Sci. 2025 Mar 11. pii: 294. [Epub ahead of print]15(3):
      As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases and mediates lactylation, an epigenetic modification that occurs under both physiological and pathological conditions. Lactylation is a crucial mechanism by which lactate exerts its functions, participating in vital biological activities such as glycolysis-related cellular functions, macrophage polarization, and nervous system regulation. Lactylation links metabolic regulation to central nervous system (CNS) diseases, such as traumatic brain injury, Alzheimer's disease, acute ischemic stroke, and schizophrenia, revealing the diverse functions of lactylation in the CNS. In the future, further exploration of lactylation-associated enzymes and proteins is needed to develop specific lactylation inhibitors or activators, which could provide new tools and strategies for the treatment of CNS diseases.
    Keywords:  central nervous system diseases; lactate; lactylation
    DOI:  https://doi.org/10.3390/brainsci15030294
  10. Microorganisms. 2025 Feb 27. pii: 527. [Epub ahead of print]13(3):
      Protein glutathionylation is defined as a reversible, ubiquitous post-translational modification, resulting in the formation of mixed disulfides between glutathione and proteins' cysteine residues. Glutathionylation has been implicated in several cellular mechanisms ranging from protection from oxidative stress to the control of cellular homeostasis and the cell cycle. A significant body of research has examined the multifaceted effects of this post-translational modification under physiological conditions in eukaryotes, with a particular focus on its impact on the development of various diseases in humans. In contrast, the role of glutathionylation in prokaryotic organisms remains to be extensively investigated. However, there has been a recent increase in the number of studies investigating this issue, providing details about the role of glutathione and other related thiols as post-translational modifiers of selected bacterial proteins. It can be concluded that in addition to the classical role of such thiols in protecting against cysteine oxidation and consequent protein inactivation, many more specialized roles of glutathionylation in bacterial pathogenicity, virulence, interspecies competition and survival, and control of gene expression are emerging, and new ones may emerge in the future. In this short review, we aim to summarize the current state-of-the-art in this field of research.
    Keywords:  GS-ylation; GSH; S-glutathionylation; glutathione; oxidative stress; post-translational modification
    DOI:  https://doi.org/10.3390/microorganisms13030527
  11. Cells. 2025 Mar 08. pii: 398. [Epub ahead of print]14(6):
      The growth of breast tumors is driven and controlled by a subpopulation of cancer cells resembling adult stem cells, which are called cancer stem-like cells (CSCs). In breast cancer, the function and maintenance of CSCs are influenced by protein O-GlcNAcylation and the enzyme responsible for this post-translational modification, O-GlcNAc transferase (OGT). However, the mechanism of CSCs regulation by OGT and O-GlcNAc cycling in breast cancer is still unclear. Analysis of the proteome and O-GlcNAcome, revealed GATAD2B, a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, as a substrate regulated by OGT. Reducing GATAD2B genetically impairs mammosphere formation, decreases expression of self-renewal factors and CSCs population. O-GlcNAcylation of GATAD2B at the C-terminus protects GATAD2B from ubiquitination and proteasomal degradation in breast cancer cells. We identify ITCH as a novel E3 ligase for GATAD2B and show that targeting ITCH genetically increases GATAD2B levels and increases CSCs phenotypes. Lastly, we show that overexpression of wild-type GATAD2B, but not the mutant lacking C-terminal O-GlcNAc sites, promotes mammosphere formation, expression of CSCs factors and drug resistance. Together, we identify a key role of GATAD2B and ITCH in regulating CSCs in breast cancer and GATAD2B O-GlcNAcylation as a mechanism regulating breast cancer stem-like populations and promoting chemoresistance.
    Keywords:  GATAD2B; NuRD; O-GlcNAc; OGT; cancer; cancer stem cell; chemoresistance; signaling
    DOI:  https://doi.org/10.3390/cells14060398
  12. Adv Sci (Weinh). 2025 Mar 27. e2413709
      Osteoarthritis (OA) progression is closely related to dysregulated glycolysis. As the primary metabolite of glycolysis, lactate plays a detrimental role in OA. However, how lactate exacerbates OA process remains unclear. Here, this study revealed that lactate levels are elevated in the synovial fluid of OA patients and IL-1β-treated human primary chondrocytes, promoting protein pan-lactylation. Functionally, hyper-lactylation exacerbates chondrocytes extracellular matrix (ECM) degradation and cell apoptosis in vitro and in vivo. Moreover, UDP-glucose dehydrogenase (UGDH) is proven to be the key lactylated protein in lactate-treated chondrocytes, which undergoes lactylation at lysine 6 (K6). Lactylated UGDH repressed its enzymatic activity, reducing glycosaminoglycan synthesis and disregulating its nuclear-cytoplasmic distribution. Mechanistically, K6 lactylation of UGDH impedes the interaction of UGDH and signal transducer and activator of transcription 1 (STAT1), thus promoting the transcription of mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and activating the MAPK signaling pathway. Importantly, in vitro and in vivo treatment with A485, a specific acyltransferase P300 inhibitor, suppressed UGDH lactylation and rescued chondrocytes ECM degradation and OA progression. These findings uncover a new mechanism underlying OA pathogenesis and highlight the potential of targeting UGDH lactylation as a novel therapeutic strategy for OA.
    Keywords:  chondrocytes; lactate; lactylation; osteoarthritis; udp‐glucose dehydrogenase
    DOI:  https://doi.org/10.1002/advs.202413709
  13. Sci Rep. 2025 Mar 24. 15(1): 10170
      Triple-negative breast cancer (TNBC) is characterized by resistance to conventional treatment and a poor prognosis. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins has been reported to affect cancer progression. However, the key O-GlcNAc proteins involved in TNBC phenotypes remain unclear. Our previous study demonstrated that serine 40 of histone H2A was modified by O-GlcNAcylation (H2AS40Gc). Since S40 is located inside the globular domain of H2A, H2AS40Gc may be involved in the regulation of gene expression by altering chromatin conformation and could serve as the molecular basis for TNBC. The present study showed that H2AS40Gc levels were significantly higher in TNBC than in the other breast cancer subtypes. Using TNBC cells in which H2AS40Gc levels were depleted, we found that H2AS40Gc is required to promote cell proliferation and migration. The underlying mechanism of this promotion involves the accumulation of H2AS40Gc in the promoter region of KDM5B, a demethylase for lysine 4 of histone H3 (H3K4) that represses the expression of KDM5B, resulting in increased H3K4 trimethylation and elevated expression of genes related to proliferation and migration. Our findings clearly indicate that H2AS40Gc functions to promote proliferation and migration through KDM5B suppression and provide new insights into potential therapeutic approaches for TNBC.
    DOI:  https://doi.org/10.1038/s41598-025-95394-z
  14. Aging Dis. 2025 Mar 26.
      Osteoporosis is a metabolic disease characterized by low bone density resulting from abnormal bone metabolism, caused by impaired osteogenesis and/or excessive bone resorption. The coordinated differentiation of osteoblasts (originating from mesenchymal stem cells) and osteoclasts (derived from hematopoietic progenitor cells) is necessary for maintaining normal bone remodeling and homeostasis. Metabolites have been confirmed to regulate cellular behavior through post-translational modifications (PTMs), including acetylation, lactylation, and succinylation. During osteoblast and osteoclast differentiation, progenitor cells undergo metabolic rewiring to meet the energy demands of these biological processes. Consequently, local metabolite profiles and intermediate metabolic products dynamically change during bone remodeling, influencing cell differentiation via PTMs. Given the regulatory role of PTMs in bone metabolism, this review systematically examines PTMs involved in osteoblast and osteoclast differentiation and explores potential avenues for addressing osteoporosis.
    DOI:  https://doi.org/10.14336/AD.2025.0123
  15. FASEB J. 2025 Mar 31. 39(6): e70493
      Emerging evidence supports the involvement of N6-Methyladenosine (m6A) modification in the etiology and progression of lung adenocarcinoma (LUAD), highlighting its potential as a therapeutic target. RNA-binding protein 15 (RBM15) is a well-known m6A writer protein that enhances global m6A methylation levels by associating with the METTL3-WTAP complex. Previous studies have demonstrated that RBM15 is upregulated and exerts an oncogenic role in LUAD by promoting the N6-methyladenosine-mediated mRNA stability. However, the regulatory mechanisms of RBM15 remain elusive. In this study, we observed that L-lactate upregulates RBM15 protein levels in non-small-cell lung cancer cell lines A549 and H23 in a time- and dosage-dependent manner. Furthermore, we discovered that lactate uptake mediated by Monocarboxylate transporter 1 (MCT1) is essential for RBM15 induction. Subsequent investigations revealed that L-lactate promotes lactylation of RBM15 majorly at Lys850 (K850), while histone deacetylase 3 (HDAC3) acts as the delactylase for RBM15. Importantly, lactylation of RBM15 stabilizes itself by inhibiting proteasome-mediated ubiquitin degradation. Mutation of the lactylation site K850R disrupts the association between RBM15 and METTL3, leading to a reduction in global m6A levels. Moreover, K850R significantly abrogated RBM15-mediated cell proliferation and migration in LUAD cells. Collectively, these findings unveil lactylation as a novel regulatory mechanism affecting both stability and m6A methylation activity of RBM15 in LUAD cells.
    Keywords:  RBM15; lactylation; m6A modification; ubiquitination degradation
    DOI:  https://doi.org/10.1096/fj.202500020RR
  16. Atherosclerosis. 2025 Mar 20. pii: S0021-9150(25)00070-X. [Epub ahead of print]403 119172
      Glycosylation is the process by which glycans (i.e. 'sugars') are enzymatically attached to proteins or lipids to form glycoconjugates. Growing evidence points to glycosylation playing a central role in atherosclerosis. Glycosylation occurs in all human cells and post-translationally modifies many signalling molecules that regulate cardiovascular disease, affecting their binding and function. Glycoconjugates are present in abundance on the vascular endothelium and on circulating lipoproteins, both of which have well-established roles in atherosclerotic plaque development. Sialic acid is a major regulator of glycan function and therefore the process of sialylation, in which sialic acid is added to glycans, is likely to be entwined in any regulation of atherosclerosis. Glycans and sialylation regulators have the potential to present as new biomarkers that predict atherosclerotic disease or as targets for pharmacological intervention, as well as providing insights into novel cardiovascular mechanisms. Moreover, the asialoglycoprotein receptor 1 (ASGR1), a glycan receptor, is emerging as an exciting new regulator of lipid metabolism and coronary artery disease. This review summarises the latest advances in the growing body of evidence that supports an important role for glycosylation and sialylation in the regulation of atherosclerosis.
    Keywords:  Atherosclerosis; Coronary artery disease; Glycans; Glycobiology; Glycosylation; Sialylation
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2025.119172
  17. Mol Cell. 2025 Mar 19. pii: S1097-2765(25)00186-8. [Epub ahead of print]
      Phosphatidylinositol 3-kinase (PI3K) phosphorylates PI(4,5)P2 to produce PI(3,4,5)P3, thereby activating AKT and other effector proteins. However, whether PI3K has non-PI(3,4,5)P3-related functions critical for tumor development remains unclear. Here, we demonstrate that high glucose induces PI3Kβ binding to O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) in glioblastoma cells, dependent on hexokinase 1 (HK1)-mediated OGT Y889 phosphorylation and subsequent p85α recruitment. Importantly, PI3Kβ functions as a protein kinase, phosphorylating OGT at T985 and enhancing OGT activity and total cellular protein O-GlcNAcylation. Activated OGT O-GlcNAcylates ATP-citrate synthase (ACLY) at T639 and S667, leading to ACLY activation-dependent acetyl-coenzyme A (CoA) production to increase fatty acid levels and histone H3 acetylation for gene transcription. Intervention in PI3Kβ-mediated OGT phosphorylation and ACLY O-GlcNAcylation inhibits glioblastoma cell proliferation and tumor growth in xenografts. These findings underscore the critical role of PI3Kβ in governing protein O-GlcNAcylation, fatty acid metabolism, and chromatin modification through its protein kinase activity and provide instrumental insight into the roles of PI3K in tumor progression.
    Keywords:  ACLY; HK1; OGT; PI3K; acetyl-CoA; fatty acid production; histone; tumor
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.024
  18. EMBO J. 2025 Mar 24.
      Lipid transfer proteins mediate the non-vesicular transport of lipids at membrane contact sites to regulate the lipid composition of organelle membranes. Despite significant recent advances in our understanding of the structural basis for lipid transfer, its functional regulation remains unclear. In this study, we report that S-palmitoylation modulates the cellular function of ATG2, a rod-like lipid transfer protein responsible for transporting phospholipids from the endoplasmic reticulum (ER) to phagophores during autophagosome formation. During starvation-induced autophagy, ATG2A undergoes depalmitoylation as the balance between ZDHHC11-mediated palmitoylation and APT1-mediated depalmitoylation. Inhibition of ATG2A depalmitoylation leads to impaired autophagosome formation and disrupted autophagic flux. Further, in cell and in vitro analyses demonstrate that S-palmitoylation at the C-terminus of ATG2A anchors the C-terminus to the ER. Depalmitoylation detaches the C-terminus from the ER membrane, enabling it to interact with phagophores and promoting their growth. These findings elucidate a S-palmitoylation-dependent regulatory mechanism of cellular ATG2, which may represent a broad regulatory strategy for lipid transport mediated by bridge-like transporters within cells.
    Keywords:  ATG2; Autophagy; Lipid Transfer Protein; S-palmitoylation
    DOI:  https://doi.org/10.1038/s44318-025-00410-7