bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–11–09
eleven papers selected by
Bruna Martins Garcia, CABIMER
  1. Lactylation in Cancer: Unlocking the Key to Drug Resistance and Therapeutic Breakthroughs.
  2. Lactylation and antitumor immunity.
  3. Lactylation Enhances the Activity of Lactate Dehydrogenase A and Promotes the Chemoresistance to Cisplatin Through Facilitating DNA Nonhomologous End Junction in Lung Adenocarcinoma.
  4. O-GlcNAcylation of DDX46 promotes hepatocellular carcinoma progression by activating the PI3K/Akt signaling pathway.
  5. Lactylation-related multigene signature in multiple myeloma: integrated prognostic stratification, immune landscape profiling, and therapeutic guidance.
  6. SLC22A6-dependent lactylation of H3K9 aggravates endothelial dysfunction and atherosclerosis.
  7. H3K18 lactylation potentiates microglial polarization via the TLR4 pathway in diabetes-induced cognitive impairment.
  8. Glycosylation as a Facile Route to Control Enzyme Orientation at Interfaces.
  9. Inhibition of BRD4 sensitizes NSCLC cells to osimertinib by suppressing APT1 and promoting MST1 palmitoylation.
  10. Clinical glycoproteomics in cancer: toward tissue-based glycoform profiling and biomarker discovery.
  11. Crucial roles of GALNT6-mediated O-glycosylation of GRP78/Bip in proliferation of breast cancer cells.
  1. Oncol Res. 2025 ;33(11): 3327-3346
    Lactylation in Cancer: Unlocking the Key to Drug Resistance and Therapeutic Breakthroughs.
    Xiangnan Feng, Dayong Li, Pingyu Wang, Xinyu Li, Guangyao Li.
      Lactylation, a post-translational modification process that adds lactate groups to lysine residues, plays a crucial role in cancer biology, especially in drug resistance. However, the specific molecular mechanisms of lactylation in cancer progression and drug resistance are still unclear, and therapeutic strategies targeting the lactylation pathway are expected to overcome metabolic reprogramming and immune evasion. Therefore, this article provides a comprehensive description and summary of lactylation modification and tumor drug resistance. Numerous studies have shown that, due to the Warburg effect, there is an abnormally high level of lactate in tumor cells. Elevated levels of lactate promote metabolic reprogramming and alter key cellular processes, including gene expression, DNA repair, and immune regulation. These cellular processes are precisely the key factors for tumor cells to develop drug resistance. Lactylation also affects the tumor microenvironment, promoting immune evasion and resistance to immunotherapy in tumor cells. This modification affects proteins involved in metabolic pathways, glycolysis, and mitochondrial function, further supporting tumor growth and metastasis. Therefore, this article provides a comprehensive description and summary of lactylation modification and tumor drug resistance to clarify the specific mechanisms between the two and provide references and directions for future research on tumor drug resistance.
    Keywords:  Lactylation; cancer metabolism; drug resistance; immune evasion; tumor microenvironment
    DOI:  https://doi.org/10.32604/or.2025.067343
  2. Front Immunol. 2025 ;16 1690068
    Lactylation and antitumor immunity.
    Biao Yang, Lingyu Li, Dongmei Shi, Tao Zhong, Huabao Xiong.
      Lactylation, a recently discovered post-translational modification (PTM), plays a critical role in cancer biology. Warburg effect induces lactate accumulation, which serves as a metabolic end-product and intercellular signaling mediator within the tumor microenvironment (TME). Beyond fueling tumor growth, elevated lactate levels drive histone and non-histone lactylation, which modulates gene expression and protein function. This epigenetic reprogramming induces immunosuppressive phenotypes in immune cells that are resident in the tumor microenvironment, including impaired effector function, enhanced immunosuppressive cytokine secretion, and altered tumor antigen presentation, collectively facilitating immune escape. This review provides a synthesis of the current understanding of lactate and lactylation in tumor immunosuppression, detailing molecular mechanisms underlying immune cell inhibition (tumor-associated macrophages, T cells, T-reg cells, NK cells and NKT cells, as well as neutrophils) and evaluating emerging therapeutic strategies (e.g., inhibitors of MCTs/LDHA, site-specific antibodies, genetic code expansion technology). We aimed to accelerate the clinical translation of lactylation-targeted anticancer therapies by highlighting recent advances.
    Keywords:  antitumor immunity; histone and non-histone lactylation; immunosuppressive phenotypes; lactate accumulation; lactylation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1690068
  3. Adv Sci (Weinh). 2025 Nov 05. e10733
    Lactylation Enhances the Activity of Lactate Dehydrogenase A and Promotes the Chemoresistance to Cisplatin Through Facilitating DNA Nonhomologous End Junction in Lung Adenocarcinoma.
    Jizhuo Li, Wenze Xun, Xijie Wang, Ruiguang Luo, Qifan Hu, Zhaocai Zhou, Jian Yuan, Yanan Wang, Xiaorui Wan, Tao Zhao, Tianyu Han, Jian-Bin Wang.
      Lactylation is a novel post-translational modification closely related to the glycolytic process, but the regulatory mechanisms between lactylation and glycolysis are far from being elucidated. Lactate dehydrogenase A (LDHA) catalyzes the formation of lactate, which provides the modifying group for protein lactylation. However, whether lactylation occurs on LDHA itself remains unknown. Here, it is found that lactylation promotes the enzymatic activity of LDHA in lung adenocarcinoma (LUAD), which in turn enhances the overall level of cellular lactylation through a positive feedback loop. Screening identified Lys81 and Lys318 as key LDHA lactylation sites, with alanyl-tRNA synthetase 1 (AARS1) serving as the mediating lactyltransferase. Mass spectrometry reveals that numerous proteins involved in DNA nonhomologous end junction (NHEJ), including FEN1, XRCC5, and XRCC6 might be regulated by lactylation. Delactylation of these proteins significantly hinders the formation of FEN1-RAD1-RAD9A-HUS1 complex, thereby leading to dysfunction of NHEJ and increasing the sensitivity of cancer cells to cisplatin. In summary, this work identifies LDHA lactylation as a critical mechanism for accelerating the progression of LUAD and reveals how this lactylation influenced cisplatin sensitivity of LUAD cells, which deepen the understanding of lactylation-mediated tumor progression and provide a potential new anticancer strategy.
    Keywords:  DNA damage repair; LDHA; glycolysis; lactylation
    DOI:  https://doi.org/10.1002/advs.202510733
  4. Biochim Biophys Acta Mol Cell Res. 2025 Oct 30. pii: S0167-4889(25)00185-5. [Epub ahead of print]1873(1): 120080
    O-GlcNAcylation of DDX46 promotes hepatocellular carcinoma progression by activating the PI3K/Akt signaling pathway.
    Qiujie Wang, Yuanyuan Liu, Kai Wang, Ailong Huang, Ni Tang, Pai Peng.
      O-linked-β-N-acetylglucosamine (O-GlcNAc) modification, also known as O-GlcNAcylation, is a dynamic and reversible protein modification. Aberrant O-GlcNAcylation are associated with the pathogenesis of cancers. DEAD-box helicase 46 (DDX46) is an ATP-dependent RNA helicase associated with cancer development; however, its role and regulation in hepatocellular carcinoma (HCC) remain unclear. In this study, we observed that the level of O-GlcNAcylation of DDX46 was significantly elevated in HCC mouse models and patients. In addition, direct OGT-DDX46 interaction facilitates O-GlcNAcylation at the Ser257 site. Mechanically, we discovered that O-GlcNAcylation enhances the stability of DDX46 by impeding ubiquitin-mediated degradation. Increased expression of DDX46 activates the PI3K/Akt signaling pathway, promoting the proliferation and invasion of HCC. Taken together, our study highlights the critical role of DDX46 O-GlcNAcylation in HCC progression, thus proposing targeted disruption of this cascade as a novel therapeutic strategy for HCC treatment.
    Keywords:  DDX46; O-GlcNAcylation; PI3K/Akt; hepatocellular carcinoma; ubiquitination
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120080
  5. Immunol Res. 2025 Nov 08. 73(1): 159
    Lactylation-related multigene signature in multiple myeloma: integrated prognostic stratification, immune landscape profiling, and therapeutic guidance.
    Wuyang Zhang, Shuai Ming, Peng Cheng, Dan Shi, Jingyu Li, Bin Wang, Yu Fang, Mengru Li, Wei Cao, Min Wang, Zaibao Wang, Jiawei Xiao, Wei Wei.
      Multiple myeloma (MM) is an incurable hematologic malignancy with high heterogeneity and poor prognosis. Lactylation, a novel post-translational modification, drives tumor progression and immune dysregulation, yet its prognostic value in MM remains uncharacterized. To explore the prognostic value of lactylation-related genes in multiple myeloma, our study aims to construct and validate a lactylation-related multigene signature, which can provide integrated prognostic stratification, immune landscape profiling, and therapeutic guidance for MM patients. This study integrated 1,417 MM patients (859 from the TCGA-MMRF training cohort; 558 from the GSE24080 validation cohort) and 121 normal controls. Differential expression identified lactylation-related genes, and a prognostic model was constructed via LASSO-Cox regression. The model was validated in an independent cohort and we assessed immune infiltration and drug sensitivity. We finally identified four lactylation-associated prognostic genes (SLC19A1, KIF23, TOP2A, and XK) and categorized the patients into high-risk/low-risk groups, which differed in survival rates (P < 0.0001). The model showed robust accuracy (3-year AUC = 0.764) and validation (P = 0.0018). Low-risk patients exhibited enhanced anti-tumor immunity (activated dendritic cells↑, CD8⁺ T cells↑) and heightened sensitivity to bortezomi/venetoclax, etc. We established the lactylation-derived gene signature for MM, providing a clinical tool for risk stratification, immune profiling, and personalized therapy.
    Keywords:  Drug sensitivity; Immune-cell infiltration; Lactylation; Multiple myeloma; Risk model
    DOI:  https://doi.org/10.1007/s12026-025-09718-2
  6. Metabolism. 2025 Nov 04. pii: S0026-0495(25)00295-1. [Epub ahead of print] 156426
    SLC22A6-dependent lactylation of H3K9 aggravates endothelial dysfunction and atherosclerosis.
    Yuting Ma, Sunye Feng, Yujie Jiang, Jingting Jiang, Ronghui Liu, Yuxin Ma, Xinglei Yin, Huimin Bian, Ruigong Zhu.
       BACKGROUND: Atherosclerosis, a leading cause of cardiovascular morbidity and mortality, is driven by endothelial dysfunction. While metabolic reprogramming toward glycolysis in endothelial cells exacerbates disease progression, the role of lactate-derived lactylation in atherogenesis remains poorly understood.
    METHODS: We performed RNA-seq on aortic tissues from atherosclerotic mice to identify differentially expressed genes, along with Seahorse XF metabolic flux analysis. Endothelium-specific solute carrier family 22 member 6 (Slc22a6) knockout and AAV-delivered acyl-CoA synthetase short-chain family member 1 (Acss1) knockdown mice were established on an ApoEKO background. Integrated multi-omics (RNA-seq, CUT&Tag, metabolomics) elucidated downstream regulatory networks, and in vivo pharmacological inhibition validated key pathways.
    RESULTS: Our study reveals a marked elevation of histone H3 Lysine 9 Lactylation (H3K9la) relative to acetylation in atherosclerotic aortic tissue, potentially via SLC22A6-mediated glycolytic enhancement and lactate uptake. Additionally, endothelial-specific knockout of Slc22a6 attenuates H3K9la-driven endothelial dysfunction and atherosclerosis. Integrated RNA-seq and CUT&Tag analyses identify that upregulated ACSS1 and E1A binding protein p300 (EP300) drive H3K9la, which transcriptionally activates stearoyl-CoA desaturase 1 (SCD1), thereby exacerbating endothelial dysfunction. Pharmacological inhibition of H3K9la or SCD1 alleviates endothelial dysfunction and atherosclerosis in vitro and in vivo. We further establish the clinical relevance of lactate, SLC22A6, and ACSS1 in atherosclerosis.
    CONCLUSIONS: Our findings unveil a metabolism-epigenetics-transcription regulatory axis in endothelial pathophysiology, thus providing novel therapeutic strategies for atherosclerosis by targeting the SLC22A6-dependent ACSS1-H3K9la-SCD1 pathway.
    Keywords:  ACSS1; Atherosclerosis; Endothelial dysfunction; H3K9 lactylation; SCD1; SLC22A6
    DOI:  https://doi.org/10.1016/j.metabol.2025.156426
  7. JCI Insight. 2025 Nov 04. pii: e188077. [Epub ahead of print]
    H3K18 lactylation potentiates microglial polarization via the TLR4 pathway in diabetes-induced cognitive impairment.
    Ying Yang, Fei Chen, Lulu Song, Liping Yu, Jinping Zhang, Bo Zhang.
      The present study aims to explore the role and possible underlying mechanisms of histone lactylation modifications in diabetes-associated cognitive impairment (DACD). In this study, behavioral tests, Hematoxylin & Eosin (HE) staining, and immunohistochemistry were used to evaluate cognitive function and the extent of cerebral tissue injury. We quantified the levels of lactic acid and Pan-lysine lactylation (Pan Kla) in the brains of type 2 diabetes mellitus (T2DM) mice and in high glucose-treated microglia. We also identified all Kla sites in isolated microglia. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were subsequently conducted to identify the functions and pathways that were enriched at the differentially expressed modification sites. cleavage under targets and tagmentation (CUT&Tag) technology was used to identify candidate genes that are regulated by H3K18la. Small interfering RNA (siRNA) and H3K18R mutant sequences were used to knock down crucial components in key signaling pathways to assess the effects of histone lactylation on microglial polarization. We found that lactic acid levels were significantly greater in the brains of T2DM mice and high glucose-treated microglia than in those of their corresponding controls, which increased the level of Pan-Kla. We discovered that lactate can directly stimulate an increase in H3K18la. The global landscape of the lactylome reveals information about modification sites, indicating a correlation between the upregulation of H3K18la and protein lactylation and Toll-like receptor signaling. CUT&Tag demonstrated that enhanced H3K18la directly stimulates the nuclear factor kappa-B (NF-κB) signaling pathway by increasing binding to the promoter of Toll Like Receptor 4 (TLR4), thereby promoting M1 microglial polarization. The present study demonstrated that enhanced H3K18la directly stimulates TLR4 signaling to promote M1 microglial polarization, thereby facilitating DACD phenotypes. Targeting such loop may be a potential therapeutic approach for the treatment of DACD.
    Keywords:  Diabetes; Endocrinology; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.188077
  8. J Phys Chem Lett. 2025 Nov 07. 11964-11969
    Glycosylation as a Facile Route to Control Enzyme Orientation at Interfaces.
    Khezar H Saeed, Sigurd F Truelsen, Tobias Weidner.
      Protein glycosylation is known to impact structural and functional dynamics, yet its influence on interfacial behavior remains underexplored. Here, we systematically investigate the effects of glycosylation on the binding orientation of the Thermomyces lanuginosus lipase (TLL) variants at the air/water interface. Using a combination of experimental vibrational sum frequency generation (VSFG) spectroscopy and spectral calculations, we directly probe the interfacial conformation of TLL with varying degrees of glycosylation. Our findings reveal that the lid-open conformation is preferred for both glycosylated and deglycosylated forms and that the N33Q point mutation does not significantly alter binding. Additionally, high-mannose glycosylation broadens the range of preferred orientations. Complementary surface pressure measurements show similar protein concentrations across variants, suggesting that the reduced VSFG intensity for glycosylated TLL arises from an increased interfacial disorder. These results demonstrate that glycosylation can indirectly modulate protein surface interactions, suggesting a broader role for this common post-translational modification in protein interfacial binding.
    DOI:  https://doi.org/10.1021/acs.jpclett.5c02420
  9. Cell Death Discov. 2025 Nov 03. 11(1): 497
    Inhibition of BRD4 sensitizes NSCLC cells to osimertinib by suppressing APT1 and promoting MST1 palmitoylation.
    Shaoqiang Wang, Yingying Zheng, Zhenyu Zhang, Lijie Qiu, Wolong Zhou, Heng Zhang.
      Osimertinib is widely used to treat non-small-cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) mutations. However, osimertinib resistance inevitably develops in almost all patients. In our study, osimertinib-resistant HCC827/OR and PC-9/OR cells were established from parental osimertinib-sensitive cells, and osimertinib (AZD9291) and NHWD870, a bromodomain and extra-terminal (BET) inhibitor, were used to treat cells and mice. PC-9/OR and HCC827/OR cells were subcutaneously injected into mice to establish a mouse model of NSCLC. Luciferase, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP) assays were applied to analyze transcription factors (TFs) binding to the APT1 promoter. MST1 palmitoylation was examined with acyl resin-assisted capture (Acyl-RAC) assays. The interaction of YAP1 and BRD4 was evaluated by co-immunoprecipitation (Co-IP) and GST-pull down assays. Our study showed that YAP1 was highly expressed, and its nuclear translocation was increased in osimertinib-resistant NSCLC cells, and silencing of YAP1 overcame osimertinib resistance. BRD4 was upregulated, and NHWD870 significantly reversed YAP1-mediated osimertinib resistance. Moreover, decreased MST1 palmitoylation at C699 was observed in NSCLC cells that are resistant to osimertinib. Furthermore, knockdown of APT1 reduced YAP1 nuclear translocation and APT1-mediated MST1 depalmitoylation restored osimertinib sensitivity. Inhibition of BRD4 blocked YAP1-mediated APT1 transcription in NSCLC cells. In addition, the BRD4 inhibitor disrupted MST1 depalmitoylation by APT1 and recovered osimertinib sensitivity. In vivo administration of NHWD870 enhanced NSCLC cell sensitivity to osimertinib. These findings indicate that inhibition of BRD4 enhances NSCLC cell sensitivity to osimertinib through the APT1-MST1-YAP1 axis. Inhibition of BRD4 sensitized non-small-cell lung cancer (NSCLC) cells to osimertinib by blocking YAP1-mediated APT1 transcription and disrupting APT1-mediated depalmitoyation of MST1 and YAP1 nuclear translocation, which restores osimertinib sensitivity through the APT1-MST1-YAP1 axis in NSCLC. Our study provides a novel mechanism of osimertinib resistance and suggests potential therapeutic strategies for NSCLC.
    DOI:  https://doi.org/10.1038/s41420-025-02794-1
  10. J Biochem. 2025 Nov 03. pii: mvaf063. [Epub ahead of print]
    Clinical glycoproteomics in cancer: toward tissue-based glycoform profiling and biomarker discovery.
    Yoshimi Haga.
      Recent advances in mass spectrometry-based proteomics have enabled increasingly precise characterization of protein modifications in clinical specimens. Among these, glycosylation is one of the most structurally complex and biologically informative post-translational modifications, reflecting cellular differentiation and disease states. Ohashi et al. (J. Biochem. 2024; 175: 561-572) performed a site-specific N-glycosylation analysis of LAMP1 in breast cancer tissue samples, demonstrating the feasibility of targeted glycoproteomics in patient-derived specimens and revealing tumor-associated glycoform heterogeneity. Their study exemplifies how focusing on a single glycoprotein target can provide detailed insight into disease-specific glycan remodeling within the tumor microenvironment. In this commentary, I discuss the significance of such targeted approaches in the broader context of clinical glycoproteomics and highlight their potential contribution to cancer biomarker discovery and precision medicine. Continued integration of glycoproteomic data with genomic and clinical information is expected to further advance our understanding of tumor biology and therapeutic response.
    Keywords:  biomarker; cancer-associated glycans; clinical proteomics; glycoproteomics; mass spectrometry
    DOI:  https://doi.org/10.1093/jb/mvaf063
  11. Biochem Biophys Res Commun. 2025 Oct 24. pii: S0006-291X(25)01584-0. [Epub ahead of print]790 152868
    Crucial roles of GALNT6-mediated O-glycosylation of GRP78/Bip in proliferation of breast cancer cells.
    Keiji Uchiyama, Kosei Hagiwara, Yosuke Matsushita, Tetsuro Yoshimaru, Masaya Ono, Mitsunori Sasa, Toyomasa Katagiri.
      Increased expression of the polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6), an O-glycosyltransferase, has been reported to play a crucial role in mammary carcinogenesis. Here, we demonstrate that GALNT6 O-glycosylates Glucose-regulated protein 78/Binding immunoglobulin protein (GRP78/Bip), a key regulator of the unfolded protein response (UPR), by adding N-acetylgalactosamine (GalNAc), thereby modulating its stability in breast cancer cells. Functional inhibition of either GALNT6 or GRP78/Bip suppressed the proliferation of the luminal-type breast cancer cell line, ZR-75-1, understanding their importance in tumor cell growth. We further found that GRP78/Bip, which is primarily localized in the endoplasmic reticulum (ER), is transported to the Golgi apparatus under the ER stress conditions, where it undergoes O-glycosylation at Thr203 by the Golgi-resident GALNT6. Substitution of Thr203 with alanine inhibited the binding of GRP78/Bip to IRE1, an ER stress sensor, suggesting that the O-glycosylation at Thr203 in GRP78/Bip facilitates sustained activation of the UPR. These findings define the GALNT6-GRP78/Bip axis as a novel mechanism driving persistent UPR activation and tumor cell adaptation to ER stress, offering a potential new therapeutic target for luminal-type breast cancers.
    Keywords:  Breast cancer; Endoplasmic reticulum stress; GALNT6; GRP78/Bip; O-Glycosylation
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152868
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