bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–04–13
eighteen papers selected by
Bruna Martins Garcia, CABIMER
  1. Emerging roles of lysine lactyltransferases and lactylation.
  2. The lactylation modification of proteins plays a critical role in tumor progression.
  3. First steps towards the design of peptides that influence the intracellular palmitoylation machinery.
  4. PBertKla: a protein large language model for predicting human lysine lactylation sites.
  5. Controlling pyroptosis through post-translational modifications of gasdermin D.
  6. Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.
  7. Zinc finger DHHC-type palmitoyltransferase 13-mediated S-palmitoylation of GNA13 from Sertoli cell-derived extracellular vesicles inhibits autophagy in spermatogonial stem cells.
  8. Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9.
  9. Lactate and Lactylation in AKI-to-CKD: Epigenetic Regulation and Therapeutic Opportunities.
  10. O-GlcNAcylation in Endocrinology: The Sweet Link.
  11. Glycolysis Induces Abnormal Transcription Through Histone Lactylation in T-lineage Acute Lymphoblastic Leukemia.
  12. Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cells.
  13. Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.
  14. Histone lactylation-augmented IRF4 is implicated in arsenite-induced liver fibrosis via modulating Th17 cell differentiation.
  15. Perturbing nuclear glycosylation in the mouse preimplantation embryo slows down embryonic development.
  16. The role of lactate metabolism in retinoblastoma tumorigenesis and ferroptosis resistance.
  17. Investigation into biased signaling, glycosylation, and drug vulnerability of acute myeloid leukemia.
  18. Design and Evaluation of Bivalent K-Ras Inhibitors that Target the CAAX Binding Site and the Acidic Surface of Farnesyltransferase and Geranylgeranyltransferase I.
  1. Nat Cell Biol. 2025 Apr;27(4): 563-574
    Emerging roles of lysine lactyltransferases and lactylation.
    Zhi Zong, Jiang Ren, Bing Yang, Long Zhang, Fangfang Zhou.
      Given its various roles in cellular functions, lactate is no longer considered a waste product of metabolism and lactate sensing is a pivotal step in the transduction of lactate signals. Lysine lactylation is a recently identified post-translational modification that serves as an intracellular mechanism of lactate sensing and transfer. Although acetyltransferases such as p300 exhibit general acyl transfer activity, no bona fide lactyltransferases have been identified. Recently, the protein synthesis machinery, alanyl-tRNA synthetase 1 (AARS1), AARS2 and their Escherichia coli orthologue AlaRS, have been shown to be able to sense lactate and mediate lactyl transfer and are thus considered pan-lactyltransferases. Here we highlight the mechanisms and functions of these lactyltransferases and discuss potential strategies that could be exploited for the treatment of human diseases.
    DOI:  https://doi.org/10.1038/s41556-025-01635-8
  2. Front Oncol. 2025 ;15 1530567
    The lactylation modification of proteins plays a critical role in tumor progression.
    Dehao Yi, Ke Zhou, Yinlong Pan, Huazhong Cai, Pan Huang.
      Lactylation modifications have been shown to be a novel type of protein post-translational modifications (PTMs), providing a new perspective for understanding the interaction between cellular metabolic reprogramming and epigenetic regulation. Studies have shown that lactylation plays an important role in the occurrence, development, angiogenesis, invasion and metastasis of tumors. It can not only regulate the phenotypic expression and functional polarization of immune cells, but also participate in the formation of tumor drug resistance through a variety of molecular mechanisms. In this review, we review the latest research progress of lactylation modification in tumors, focusing on its mechanism of action in angiogenesis, immune cell regulation in tumor microenvironment (TME), and tumor drug resistance, aiming to provide a theoretical basis and research ideas for the discovery of new therapeutic targets and methods. Through the in-depth analysis of lactylation modification, it is expected to open up a new research direction for tumor treatment and provide potential strategies for overcoming tumor drug resistance and improving clinical efficacy.
    Keywords:  Angiogenesis; Drug Resistance; TME Warburg effect and lactylation; lactylation modification; tumor
    DOI:  https://doi.org/10.3389/fonc.2025.1530567
  3. Chembiochem. 2025 Apr 10. e202500218
    First steps towards the design of peptides that influence the intracellular palmitoylation machinery.
    Ines Neundorf, Katharina Stillger, Eric Platz-Baudin, Florian Friedland, Melina Ruppel, Coco-Louisa Sticker, Anne Bodenhausen, Eric Noetzel.
      Protein S-palmitoylation is a reversible post-translational modification transferring the 16-carbon fatty acid palmitate to cysteines. It plays a critical role in many cellular processes by influencing protein function, localization, stability, and protein-protein interactions and has a significant impact on various physiological and pathological conditions. This emphasizes the need to develop new technologies to study and treat diseases associated with aberrant palmitoylation. To address these challenges, we present cell-permeable peptides containing a DHHC palmitoylation motif aiming to affect intracellular protein S-palmitoylation. A small library of peptides was generated and screened for cellular uptake and cell compatibility. Interestingly, the newly designed peptides internalized to high extent into different cell lines and human breast cell spheroids dependent on their palmitoylation motif. In addition, out of this screen we identified DC-2 as very potent and investigated this peptide in more detail concerning its impact on palmitoylated proteins that are connected to cancer progression. These initial explorations highlighted that DC-2 affected the localization of HRas and altered S-palmitoylation-related signaling cascades of EGFR. Our findings suggest a peptide-driven impact on proteins having palmitoylation sites and highlight cell-permeable DHHC-peptides as a potential tool to be further evolved in the context of palmitoylation and cancer.
    Keywords:  EGF receptor; Peptides; ZDHHC enzymes; cysteine palmitoylation; protein modification
    DOI:  https://doi.org/10.1002/cbic.202500218
  4. BMC Biol. 2025 Apr 07. 23(1): 95
    PBertKla: a protein large language model for predicting human lysine lactylation sites.
    Hongyan Lai, Diyu Luo, Mi Yang, Tao Zhu, Huan Yang, Xinwei Luo, Yijie Wei, Sijia Xie, Feitong Hong, Kunxian Shu, Fuying Dao, Hui Ding.
       BACKGROUND: Lactylation is a newly discovered type of post-translational modification, primarily occurring on lysine (K) residues of both histones and non-histones to exert diverse effects on target proteins. Research has shown that lysine lactylation (Kla) modification is ubiquitous in different cells and participates in the determination of cell function and fate, as well as in the initiation and progression of various diseases. Precise identification of Kla sites is fundamental for elucidating their biological functions and uncovering their application potential.
    RESULTS: Here, we proposed a novel human Kla site predictor (named PBertKla) through curating a reliable benchmark dataset with proper sample length and sequence identity threshold to train a protein large language model with optimal hyperparameters. Extensive experimental results consistently demonstrated that our model possessed robust human Kla site prediction ability, achieving an AUC (area under receiver operating characteristic curve) value of over 0.880 on the independent validation data. Feature visualization analysis further validated the effectiveness of in feature learning and representation from Kla sequences. Moreover, we benchmarked PBertKla against other cutting-edge models on an independent testing dataset from different sources, highlighting its superiority and transferability.
    CONCLUSIONS: All results indicated that PBertKla excelled as an automatic predictor of human Kla sites, and it would advance the investigation of lactylation modifications and their significance in health and disease.
    Keywords:  BERT; Human; Lysine lactylation site; Protein large language model; Transformer
    DOI:  https://doi.org/10.1186/s12915-025-02202-1
  5. Dev Cell. 2025 Apr 07. pii: S1534-5807(25)00067-X. [Epub ahead of print]60(7): 994-1007
    Controlling pyroptosis through post-translational modifications of gasdermin D.
    Na Zhang, Daichao Xu.
      Pyroptosis, a lytic and programmed cell death pathway, is mediated by gasdermins (GSDMs), with GSDMD playing an important role in innate immunity and pathology. Upon activation, GSDMD is cleaved to release the active N-terminal fragment that oligomerizes into membrane pores, which promote pyroptosis and cytokine secretion, leading to inflammation. Emerging evidence indicates that post-translational modification (PTM) is an important regulatory mechanism of GSDMD activity. This review explores how PTMs, aside from proteolytic cleavage, control GSDMD activity and link biological contexts to pyroptosis in innate immunity and inflammation, which could inform future studies and therapeutic solutions for treating inflammatory conditions.
    Keywords:  GSDMD; gasdermin; palmitoylation; phosphorylation; pore forming; post-translational modification; pyroptosis; ubiquitination
    DOI:  https://doi.org/10.1016/j.devcel.2025.02.005
  6. Cell Oncol (Dordr). 2025 Apr 07.
    Sirtuin 3-mediated delactylation of malic enzyme 2 disrupts redox balance and inhibits colorectal cancer growth.
    Chaoqun Li, Cun Ge, Qingwen Wang, Peng Teng, Heyuan Jia, Surui Yao, Zhaohui Huang.
       PURPOSE: Post-translational modifications, such as lactylation, are emerging as critical regulators of metabolic enzymes in cancer progression. Mitochondrial malic enzyme 2 (ME2), a key enzyme in the TCA cycle, plays a pivotal role in maintaining redox homeostasis and supporting tumor metabolism. However, the functional significance of ME2 lactylation and its regulatory mechanisms remain unclear. This study investigates the role of ME2 K352 lactylation in modulating enzymatic activity, redox balance, and tumor progression.
    METHODS: Immunoprecipitation and western blotting were used to assess ME2 lactylation and its interaction with Sirtuin 3 (SIRT3). Mass spectrometry identified the lactylation site on ME2. Enzymatic activity was measured using NADH production assays. The functional effects of ME2 K352 lactylation were analyzed by measuring ROS levels, NADP⁺/NADPH ratios, metabolic intermediates, and mitochondrial respiration parameters. Cell proliferation was evaluated via CCK-8 and colony formation assays. Xenograft tumor models and Ki-67 immunohistochemical staining were used to assess tumor growth and proliferation in vivo.
    RESULTS: Mass spectrometry identified K352 as the primary lactylation site on ME2. Sodium lactate treatment enhanced ME2 lactylation and enzymatic activity, while SIRT3-mediated delactylation at K352 reduced ME2 activity, disrupting redox homeostasis. Cells expressing the K352R mutant exhibited elevated ROS levels, higher NADP⁺/NADPH ratios, and altered levels of metabolic intermediates, including increased malate and lactate with reduced pyruvate. Additionally, re-expression of ME2 K352R in HCT116 cells significantly impaired proliferation and colony formation. In vivo, xenograft models demonstrated that ME2 K352R expression suppressed tumor growth, as evidenced by reduced tumor volume, weight, and Ki-67 staining.
    CONCLUSIONS: This study reveals that ME2 K352 lactylation is a critical regulatory mechanism that modulates enzymatic activity, mitochondrial function, and tumor progression. SIRT3-mediated delactylation of ME2 K352 disrupts redox homeostasis and inhibits tumor growth. These findings highlight the potential of targeting ME2 lactylation as a therapeutic strategy in cancer treatment.
    Keywords:  Cancer metabolism; Lactylation; ME2; Mitochondrion; Posttranslational modification; SIRT3
    DOI:  https://doi.org/10.1007/s13402-025-01058-5
  7. Cell Commun Signal. 2025 Apr 09. 23(1): 178
    Zinc finger DHHC-type palmitoyltransferase 13-mediated S-palmitoylation of GNA13 from Sertoli cell-derived extracellular vesicles inhibits autophagy in spermatogonial stem cells.
    Heran Cao, Huihui Gao, Yan Li, Long Li, Shujuan Liu, Tianqi Jin, Yang Wang, Ye Gong, Shuiqiao Yuan, Wuzi Dong.
      Extracellular vesicles (EVs) originating from testicular somatic cells act as pivotal intermediaries in cell signaling crosstalk between spermatogenic cells and the testicular microenvironment. The intricate balance between palmitoylation and depalmitoylation governs the positioning of protein cargos on the membrane, thereby influencing cellular activities by concentrating these proteins in EVs for delivery to recipient cells. Here, we reveal that GNA13 undergoes specific S-palmitoylation at Cys14 and Cys18 residues in Sertoli cells (SCs), a modification essential for its localization to the plasma membrane. We identify DHHC13, a member of the zinc finger DHHC-type palmitoyltransferase family that catalyzes protein S-palmitoylation, as the enzyme responsible for this critical post-translational modification. Additionally, GNA13 palmitoylation is indispensable for its selective enrichment in EVs emanating from SCs. Intriguingly, we discovered the presence of palmitoylated GNA13 in SC-derived EVs significantly downregulates autophagy levels in spermatogonial stem cells (SSCs), and the inhibition of GNA13 palmitoylation attenuates its interaction with ARHGEF12 which leads to diminished RhoA activity and consequent elevation of autophagy in SSCs. Our results illuminate the crucial role of DHHC13-mediated GNA13 S-palmitoylation in modulating autophagy levels in SSCs through SCs-derived EVs, suggesting that PM-GNA13-EV may serve as a potential candidate for further exploration in addressing fertility-related challenges during spermatogenesis.
    Keywords:  Autophagy; Extracellular vesicles; GNA13; Palmitoylation; Sertoli cells; Spermatogonial stem cells
    DOI:  https://doi.org/10.1186/s12964-025-02177-0
  8. Front Pharmacol. 2025 ;16 1559744
    Gastrodin attenuates rheumatoid arthritis by targeting KAT8 to inhibit the lactylation of H3K9.
    Yufang Dai, Shunshun Wang, Jiayi Luo, Huiming Yu, Qianqian Du, Shuwan Hou, Minfu Liu, Shan Jiang, Huajiao Xu, Siyi Ye, Muhammad Farrukh Nisar, Haiyan Chen, Jiaqin Wu.
      Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction, with limited therapeutic options. This study investigated the therapeutic potential of gastrodin (GAS), a natural phenolic glycoside derived from Gastrodia elata, in targeting lysine acetyltransferase 8 (KAT8) to suppress histone H3K9 lactylation (H3K9la), a novel post-translational modification linked to inflammatory responses. Methods: The therapeutic effect of GAS on RA was verified by constructing RA models in vivo and in vitro. Molecular docking, surface plasmon resonance (SPR) assays, overexpression and silencing experiments were used to verify the results. Results: In vitro experiments demonstrated that GAS (10-20 μM) significantly inhibited lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines (IL-6, MMP1, MMP13) in fibroblast-like synoviocytes (FLS) and THP-1 macrophages by downregulating glycolysis and lactate production. Molecular docking and surface plasmon resonance (SPR) assays confirmed KAT8 as a direct target of GAS, with a dissociation constant (K D ) of 413.72 μM. Overexpression and silencing experiments revealed that GAS destabilized KAT8, thereby reducing H3K9la levels. In vivo, GAS (20 mg/kg) ameliorated joint swelling and synovial hyperplasia in a Sprague-Dawley rat adjuvant-induced arthritis (AIA) model, correlating with decreased H3K9la and IL-6 expression. Discussion: These findings establish GAS as a promising therapeutic agent for RA by modulating KAT8-mediated histone lactylation, providing new insights into epigenetic regulation of inflammation.
    Keywords:  H3K9; KAT8; gastrodin; glycolysis; histone lactylation; rheumatoid arthritis
    DOI:  https://doi.org/10.3389/fphar.2025.1559744
  9. Cell Prolif. 2025 Apr 10. e70034
    Lactate and Lactylation in AKI-to-CKD: Epigenetic Regulation and Therapeutic Opportunities.
    Yi Hou, Dongwei Liu, Zuishuang Guo, Cien Wei, Fengyu Cao, Yue Xu, Qi Feng, Fengxun Liu.
      Lactate is not only a byproduct of glycolysis, but is also considered an energy source, gluconeogenic precursor, signalling molecule and protein modifier during the process of cellular metabolism. The discovery of lactylation reveals the multifaceted functions of lactate in cellular metabolism and opens new avenues for lactate-related research. Both lactate and lactylation have been implicated in regulating numerous biological processes, including tumour progression, ischemic-hypoxic injury, neurodevelopment and immune-related inflammation. The kidney plays a crucial role in regulating lactate metabolism, influencing lactate levels while also being regulated by lactate. Previous studies have demonstrated the importance of lactate in the pathogenesis of acute kidney injury (AKI) and chronic kidney disease (CKD). This review explores the role of lactate and lactylation in these diseases, comparing the function and metabolic mechanisms of lactate in normal and diseased kidneys from the perspective of lactylation. The key regulatory roles of lactylation in different organs, multiple systems, various pathological states and underlying mechanisms in AKI-to-CKD progression are summarised. Moreover, potential therapeutic targets and future research directions for lactate and lactylation across multiple kidney diseases are identified.
    Keywords:  acute kidney injury (AKI); chronic kidney disease (CKD); lactate; lactylation
    DOI:  https://doi.org/10.1111/cpr.70034
  10. Endocrinology. 2025 Apr 10. pii: bqaf072. [Epub ahead of print]
    O-GlcNAcylation in Endocrinology: The Sweet Link.
    Adam S Knier, Stephanie Olivier-Van Stichelen.
      O-GlcNAcylation is a dynamic post-translational modification that involves the addition of N-acetylglucosamine (GlcNAc) to the serine and threonine residues of proteins. Over the past four decades, this modification has become increasingly recognized as having a critical influence in the field of endocrinology. The carefully controlled hormonal input for regulating sleep, mood, response to stress, growth and development, and metabolism are often associated with O-GlcNAc-dependent signaling. As protein O-GlcNAcylation patterns are heavily dependent on environmental glucose concentrations, hormone-secreting cells sense the changes in local environmental glucose concentrations and adjust hormone secretion accordingly. This ability of cells to sense nutritional cues and fine-tune hormonal production is particularly relevant towards maintaining a functional and responsive endocrine system, therefore emphasizing the importance of O-GlcNAc in the scope and application of endocrinology. This review examines how O-GlcNAcylation participates in hormonal homeostasis in different endocrine tissues and systems, from the pineal gland to the placenta, and underscores the significance of O-GlcNAc in the field of endocrinology.
    Keywords:   O-GlcNAc; Endocrinology; Growth; Hormones; Metabolism; Stress
    DOI:  https://doi.org/10.1210/endocr/bqaf072
  11. Genomics Proteomics Bioinformatics. 2025 Apr 07. pii: qzaf029. [Epub ahead of print]
    Glycolysis Induces Abnormal Transcription Through Histone Lactylation in T-lineage Acute Lymphoblastic Leukemia.
    Wenyan Wu, Jingyi Zhang, Huiying Sun, Xiaoyu Wu, Han Wang, Bowen Cui, Shuang Zhao, Kefei Wu, Yanjun Pan, Rongrong Fan, Ying Zhong, Xiang Wang, Ying Wang, Xiaoxiao Chen, Jianan Rao, Ronghua Wang, Kai Luo, Xinrong Liu, Liang Zheng, Shuhong Shen, Meng Yin, Yangyang Xie, Yu Liu.
      The Warburg effect, which excessively produce lactate, and transcriptional dysregulation are two hallmarks of tumors. However, the precise influence of lactate on epigenetic modifications at a genome-wide level and its impact on gene transcription in tumor cells remain unclear. We conducted an analysis of genome-wide histone H3 lysine 18 lactylation (H3K18la) modifications in T-cell acute lymphoblastic leukemia (T-ALL). We found an increased level of lactate and H3K18la in T-ALL tumor cells compared to normal T cells and the H3K18la modification is associated with cell proliferation. Accordingly, we observed a significant shift in genome-wide H3K18la modification from T cell immunity in normal T cells to leukemogenesis in T-ALL, which correlated with altered gene transcription profiles. We showed that H3K18la is primarily involved in actively regulating gene transcription and observed clusters of H3K18la modifications exhibiting patterns reminiscent of super-enhancers. Disrupting H3K18la modification revealed both synergistic and divergent changes between H3K18la and histone H3 lysine 27 acetylation (H3K27ac) modifications. Finally, we found that the high transcription of H3K18la target genes, IGFBP2 and IARS, is associated with inferior prognosis of T-ALL. These findings enhance our understanding of how metabolic disruptions contribute to transcription dysregulation through epigenetic changes in T-ALL, underscoring the interplay of histone modifications in maintaining oncogenic epigenetic stability.
    Keywords:  Histone H3 lysine 18 lactylation; Metabolism epigenetic interplay; Pediatric T-cell acute lymphoblastic leukemia; Transcription dysregulation; Warburg effect
    DOI:  https://doi.org/10.1093/gpbjnl/qzaf029
  12. Cell Death Differ. 2025 Apr 04.
    Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cells.
    Yiming Tu, Lei Xu, Guoqiang Fu, Jichen Wang, Pengfei Xia, Zeqiang Tao, Yangfan Ye, Jingming Hu, Wanzhi Cai, Hang Zhu, Qing Wu, Jing Ji.
      Glioblastoma (GBM) is the most primary lethal brain cancer, characterized by the presence of glioblastoma stem cells (GSCs) that initiate and sustain tumor growth and induce radioresistance. Annexin A2 (ANXA2) has been reported to contribute to glioblastoma progression and impart stem cell-like properties to GSCs, however, its post-translational modifications and mechanisms in GSCs maintenance remain poorly understood. Here, we identify that USP4 is preferentially expressed by GSCs in GBM, USP4/ANXA2 supports GSCs maintenance and radioresistance. Specifically, USP4 interacts with ANXA2, stabilizing its protein by deubiquitinating ANXA2, which mediates its proteasomal degradation and Y24 phosphorylation. USP4 directly cleaves Lys48- and Lys63-linked polyubiquitin chains of ANXA2, with the Lys63-linked polyubiquitin chains of ANXA2 K28 mediating its Y24 phosphorylation. Moreover, K10 acetylation of ANXA2 enhances its interaction with USP4. Importantly, USP4/ANXA2 promotes GSCs maintenance and radioresistance by activating BMX-mediated STAT3 activation. H3K18 lactylation is responsible for the upregulation of USP4 in GSCs. Our studies reveal that USP4/ANXA2 plays critical roles in maintaining GSCs and therapeutic resistance, highlighting the importance of lactylation, acetylation, ubiquitination, and phosphorylation as critical post-translational modifications for USP4-mediated stabilization and activity of ANXA2.
    DOI:  https://doi.org/10.1038/s41418-025-01494-8
  13. Nat Commun. 2025 Apr 04. 16(1): 3230
    Lactate activates trained immunity by fueling the tricarboxylic acid cycle and regulating histone lactylation.
    Huanhuan Cai, Xueyuan Chen, Yan Liu, Yingbo Chen, Gechang Zhong, Xiaoyu Chen, Shuo Rong, Hao Zeng, Lin Zhang, Zelong Li, Aihua Liao, Xiangtai Zeng, Wei Xiong, Cihang Guo, Yanfang Zhu, Ke-Qiong Deng, Hong Ren, Huan Yan, Zeng Cai, Ke Xu, Li Zhou, Zhibing Lu, Fubing Wang, Shi Liu.
      Trained immunity refers to the long-term memory of the innate immune cells. However, little is known about how environmental nutrient availability influences trained immunity. This study finds that physiologic carbon sources impact glucose contribution to the tricarboxylic acid (TCA) cycle and enhance cytokine production of trained monocytes. Our experiments demonstrate that trained monocytes preferentially employe lactate over glucose as a TCA cycle substrate, and lactate metabolism is required for trained immune cell responses to bacterial and fungal infection. Except for the contribution to the TCA cycle, endogenous lactate or exogenous lactate also supports trained immunity by regulating histone lactylation. Further transcriptome analysis, ATAC-seq, and CUT&Tag-seq demonstrate that lactate enhance chromatin accessibility in a manner dependent histone lactylation. Inhibiting lactate-dependent metabolism by silencing lactate dehydrogenase A (LDHA) impairs both lactate fueled the TCA cycle and histone lactylation. These findings suggest that lactate is the hub of immunometabolic and epigenetic programs in trained immunity.
    DOI:  https://doi.org/10.1038/s41467-025-58563-2
  14. Chem Biol Interact. 2025 Apr 08. pii: S0009-2797(25)00137-1. [Epub ahead of print] 111507
    Histone lactylation-augmented IRF4 is implicated in arsenite-induced liver fibrosis via modulating Th17 cell differentiation.
    Weiyong Chen, Peiwen Wang, Yan Xie, Daxiao Xie, Hailan Wang, Ning Bu, Jiaheng Lin, Meng Wu, Haibo Xia, Cheng Cheng, Yuanzhong Zhou, Qizhan Liu.
      Arsenic, a ubiquitous environmental toxicant, has been implicated in causing liver fibrosis through chronic exposure. Histone lactylation is involved in various inflammatory diseases, among which liver fibrosis is included, and is also closely related to the regulation of immune cells. This work focuses on the mechanisms of histone lactylation and Th17 cell differentiation in arsenite-induced liver fibrosis through animal and cellular experiments. Chronic arsenite exposure of mice led to liver fibrosis, elevated glycolysis in liver, and increased lactate levels in both serum and liver, which promoted Th17 cell differentiation of CD4+ T cells and increased IL-17A secretion. Treatment with oxamate, a lactate dehydrogenase inhibitor, suppressed Th17 cell differentiation and alleviated fibrosis in the liver. For HepG2 cells, arsenite exposure enhanced glycolysis and lactate levels, leading to increased Kla (global lactylation), H3K18la, IRF4 (interferon-regulatory factor 4), RORγt (retinoic acid receptor-related orphan receptor gamma t), and IL-17A expression and secretion in co-cultured Jurkat cells. Furthermore, in Jurkat cells, reducing lactate production and transport decreased these protein levels, suppressed Th17 cell differentiation, decreased IL-17A secretion, and ultimately inhibited the activation of hepatic stellate cells. These results indicate that lactate derived from hepatocytes promotes Th17 cell differentiation by upregulating IRF4 through H3K18la, thereby enhancing IL-17A secretion and the activation of hepatic stellate cells, contributing to arsenite-induced liver fibrosis. Our work reveals a new mechanism of histone lactylation in arsenite-induced liver fibrosis and offers a fresh perspective for the development of strategies for prevention and treatment of this condition.
    Keywords:  Arsenite; Hepatic stellate cells activation; Histone lactylation; Liver fibrosis; Th17 cell differentiation
    DOI:  https://doi.org/10.1016/j.cbi.2025.111507
  15. Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2410520122
    Perturbing nuclear glycosylation in the mouse preimplantation embryo slows down embryonic development.
    Sara Formichetti, Joana B Serrano, Urvashi Chitnavis, Agnieszka Sadowska, Na Liu, Ana Boskovic, Matthieu Boulard.
      The main form of intracellular protein glycosylation (O-GlcNAc) is reversible and has been mapped on thousands of cytoplasmic and nuclear proteins, including RNA polymerase II, transcription factors, and chromatin modifiers. The O-GlcNAc modification is catalyzed by a single enzyme known as O-GlcNAc Transferase, that is required for mammalian early development. Yet, neither the regulatory function of protein O-GlcNAcylation in the embryo nor the embryonic O-GlcNAc proteome have been documented. Here, we devised a strategy to enzymatically remove O-GlcNAc from preimplantation embryonic nuclei, where this modification accumulates coincidently with embryonic genome activation (EGA). Unexpectedly, the depletion of nuclear O-GlcNAc to undetectable levels has no impact on EGA, but dampens the transcriptional upregulation of the translational machinery, and triggers a spindle checkpoint response. These molecular alterations were phenotypically associated with a developmental delay starting from early cleavage stages and persisting after embryo implantation, establishing a link between nuclear glycosylation and the pace of embryonic development.
    Keywords:  O-GlcNAc; embryonic genome activation; gene expression; preimplantation development
    DOI:  https://doi.org/10.1073/pnas.2410520122
  16. Tissue Cell. 2025 Apr 01. pii: S0040-8166(25)00173-9. [Epub ahead of print]95 102893
    The role of lactate metabolism in retinoblastoma tumorigenesis and ferroptosis resistance.
    Zhihui Zhang, Junjie Tang, Yaoming Liu, Yinghao Wang, Jinmiao Li, Yang Gao, Chao Cheng, Shicai Su, Shuxia Chen, Siming Ai, Ping Zhang, Rong Lu.
      The Warburg effect, a hallmark of cancer, describes the preference of cancer cells for glucose metabolism via aerobic glycolysis, leading to substantial lactate accumulation. However, the role of lactate metabolism in retinoblastoma, the primary intraocular malignancy in children, remains unclear. This study aimed to elucidate the gene expression profiles associated with lactate metabolism in retinoblastoma and their impact on tumorigenesis and ferroptosis resistance. The involvement of metabolic characteristics in retinoblastoma was analyzed by comparing single-cell RNA sequencing transcriptome profiles from normal retina tissues and retinoblastoma tissues from patient samples. The effects of lactate on retinoblastoma cell line viability and its mechanisms were examined both in vitro and in vivo. Single-cell RNA sequencing analysis revealed enhanced glycolysis in retinoblastoma cells and significant differences in lactate metabolism-related gene expression among various retinoblastoma cell types. Retinoblastoma cell lines with moderate lactate levels exhibited increased viability and resistance to ferroptosis induced by ferroptosis inducers. Additionally, lactate promoted the upregulation of monocarboxylate transporter 1 (MCT1), which facilitated lactate transport, in a dose-dependent manner in retinoblastoma cell lines. Knocking down MCT1 reduced both viability and ferroptosis resistance of retinoblastoma cell lines in a lactate-rich environment. In vivo, disrupting lactate transport through MCT1 inhibition suppressed retinoblastoma tumorigenesis and invasion in a mouse xenograft model, and this effect was reversed by the ferroptosis inhibitor liproxstatin-1. These findings highlighted the crucial role of lactate metabolism in retinoblastoma tumorigenesis and resistance to ferroptosis.
    Keywords:  Ferroptosis; Lactate metabolism; Monocarboxylate transporter 1; Retinoblastoma
    DOI:  https://doi.org/10.1016/j.tice.2025.102893
  17. Pharmacol Ther. 2025 Apr 05. pii: S0163-7258(25)00060-9. [Epub ahead of print]270 108848
    Investigation into biased signaling, glycosylation, and drug vulnerability of acute myeloid leukemia.
    Tomasz Pienkowski, Aleksandra Golonko, Lukasz Bolkun, Katarzyna Wawrzak-Pienkowska, Lukasz Szczerbinski, Adam Kretowski, Michal Ciborowski, Wlodzimierz Lewandowski, Waldemar Priebe, Renata Swislocka.
      Understanding and harnessing biased signaling offers significant potential for developing novel therapeutic strategies or enhancing existing treatments. By managing biased signaling, it is possible to minimize adverse effects, including toxicity, and to optimize therapeutic outcomes by selectively targeting beneficial pathways. In the context of acute myeloid leukemia (AML), a highly aggressive blood cancer characterized by the rapid proliferation of abnormal myeloid cells in the bone marrow and blood, the dysregulation of these signaling pathways, particularly those involving G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), significantly contributes to disease progression and therapeutic resistance. Traditional therapies for AML often struggle with resistance and toxicity, leading to poor patient outcomes. However, by exploiting the concept of biased signaling, researchers may be able to design drugs that selectively activate pathways that inhibit cancer cell growth while avoiding those that contribute to resistance or toxicity. Glycosylation, a key post-translational modification (PTM), plays a crucial role in biased signaling by altering receptor conformation and ligand-binding affinity, thereby affecting the outcome of biased signaling. Chemokine receptors like CXCR4, which are often overexpressed and heavily glycosylated in AML, serve as targets for therapeutic intervention. By externally inducing or inhibiting specific PTMs, it may be possible to further refine therapeutic strategies, unlocking new possibilities for developing more effective and less toxic treatments. This review highlights the importance of understanding the dynamic relationship between glycosylation and biased signaling in AML, which is essential for the development of more effective treatments and overcoming drug resistance, ultimately leading to better patient outcomes.
    Keywords:  Biased ligand; Biased receptor; Biased signaling; Drug development; G protein-coupled receptor; Tyrosine kinase receptor
    DOI:  https://doi.org/10.1016/j.pharmthera.2025.108848
  18. Chemistry. 2025 Apr 09. e202500306
    Design and Evaluation of Bivalent K-Ras Inhibitors that Target the CAAX Binding Site and the Acidic Surface of Farnesyltransferase and Geranylgeranyltransferase I.
    Junko Ohkanda, Naomi Horiuchi, Rania Omer, Fumitoshi Sugino, Naomi Ogino, Yoshihisa Inoue, Kazi Aslamuzzaman, Takeyuki Suzuki, Said Sebti.
      Mutant K-Ras drives cancer through its membrane localization, which requires post-translational modification by farnesyltransferase (FTase). FTase attaches farnesyl to the K-Ras C-terminal CVIM tetrapeptide, enabling membrane binding. However, K-Ras can also undergo compensatory geranylgeranylation by geranylgeranyltransferase I (GGTase I), making FTase inhibition alone ineffective. Dual inhibition of FTase and GGTase I is necessary to fully block K-Ras localization and its cancer activity. We developed bivalent inhibitors targeting both FTase and GGTase I by binding to the CVIM site and an adjacent acidic surface. A non-thiol CVIM peptidomimetic based on a piperidine scaffold showed potent FTase inhibition (Ki = 2.1 nM) with less effect on GGTase I (Ki = 210 nM). Adding cationic modules to this compound produced dual inhibitors with enhanced potency (Ki = 2-5 nM), significantly improving upon previous agents. These bivalent inhibitors effectively reduced mutant K-Ras cancer cell viability and inhibited K-Ras farnesylation and geranylgeranylation in cells. This dual-targeting approach shows promise for treating K-Ras-driven cancers.
    Keywords:  K-Ras, posttranslational lipid modification, bivalent inhibitors, dual inhibition, farnesyltransferase, geranylgeranyltransferase, peptidomimetics
    DOI:  https://doi.org/10.1002/chem.202500306
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