bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–10–12
nine papers selected by
Bruna Martins Garcia, CABIMER
  1. Palmitoylation modulates antitumor immunity.
  2. Metabolite to Modifier: Lactate and Lactylation in the Evolution of Tumors.
  3. PSMD14-Mediated LDHA Deubiquitination Upregulates ACLY Expression via H3K18 Lactylation to Promote Lipid Synthesis and Pancreatic Cancer Progression.
  4. Post-translational acylation modulates immunosuppression and immunotherapy efficacy in hepatocellular carcinoma.
  5. ZDHHC5 as a central regulator in a palmitoylation-associated prognostic model for lung adenocarcinoma: insights from pan-cancer and experimental analyses.
  6. Asparagine-linked glycosylation protein 1 (ALG1) promotes aggressive phenotypes of lung adenocarcinoma cells, A549, via modulating N-linked glycosylation and ER-Stress.
  7. Insights into O-GlcNAcylation and programmed cell death in cancer.
  8. Acetylation-dependent USP7-TRIM25 axis drives oncogenic progression in non-small cell lung cancer.
  9. O-GlcNAcylation of UGDH regulates its activity and remodels the extracellular matrix to facilitate tumor growth.
  1. Mol Biol Rep. 2025 Oct 09. 52(1): 991
    Palmitoylation modulates antitumor immunity.
    Feng Tang, Jia-Long Xu, Qing Zhang, Xi Chen, Ze-Fen Wang, Ya-Di Xu, Zhi-Qiang Li.
      Immune checkpoints (ICs) maintain immune homeostasis by suppressing excessive T-cell activation. Their dysregulated expression or signaling facilitates tumor immune evasion, thereby undermining the effectiveness of cancer immunotherapies. Palmitoylation, a reversible post-translational modification, covalently attaches palmitate to cysteine residues, altering protein localization, stability, and function. Recent studies have indicated that palmitoylation of the IC-related signaling pathway governs their membrane trafficking, signaling activity, and interactions with effector molecules, ultimately shaping anti-tumor immune responses. This review integrates the current understanding of palmitoylation mechanisms, examines their role in IC regulation, explores potential immunotherapeutic applications, and highlights future research directions.
    Keywords:  Immunotherapy; Palmitoylation; Post-translational; Tumor
    DOI:  https://doi.org/10.1007/s11033-025-11084-z
  2. MedComm (2020). 2025 Oct;6(10): e70413
    Metabolite to Modifier: Lactate and Lactylation in the Evolution of Tumors.
    Long Zhao, Haoyue Cui, Yutong Li, Yingjiang Ye, Zhanlong Shen.
      Lactate, once dismissed as a mere by-product of cancer metabolism, has emerged as a pivotal factor in tumor progression, exerting diverse effects on metabolic reprogramming and immune modulation. Lactate enhances tumor cell adaptability through sustained glycolysis and concurrently shapes the tumor microenvironment by modulating immune, stromal, and endothelial cell function. This review highlights the evolving understanding of lactate's role, extending beyond the Warburg effect to its regulatory capacity via lactylation, a recently identified post-translational modification. The complex interaction between lactate and tumor biology is examined, emphasizing its influence on the tumor microenvironment and immune dynamics. Additionally, potential therapeutic strategies targeting lactate metabolism and transport are explored, along with lactylation regulation by histone-modifying enzymes. Inhibitors targeting lactate production and transport, especially those against lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), have shown considerable potential in preclinical and early clinical studies. Recent advancements are discussed, underscoring the potential of integrating metabolic regulation with immunotherapies, thereby offering a dual pathway in cancer treatment. These insights establish lactate and lactylation as pivotal modulators of tumor biology and highlight their potential as targets in precision oncology.
    Keywords:  cancer therapy; immune modulation; lactate; lactylation; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.70413
  3. Adv Sci (Weinh). 2025 Oct 06. e05762
    PSMD14-Mediated LDHA Deubiquitination Upregulates ACLY Expression via H3K18 Lactylation to Promote Lipid Synthesis and Pancreatic Cancer Progression.
    Ri-Shang Lu, Li-Kun Ren, Xiao-Bin Fei, Song-Bai Liu, Yong-Jia Gao, Jun-Yi Hou, Chi Wang, Peng Liu, Chang-Hao Zhu, Xing Wang, Yao-Zhen Pan.
      Aberrant lipid metabolism is intimately linked to tumor progression. As a pivotal post-translational modification, ubiquitination regulates diverse oncogenic processes. However, the interplay between ubiquitination and lipid metabolic dysregulation in pancreatic cancer (PC), along with its underlying molecular mechanisms, remains poorly understood. Here, it is demonstrated that glycolytic enzyme lactate dehydrogenase A (LDHA) potentiates lipid biosynthesis under the regulation of deubiquitinases. Specifically, PSMD14 directly binds and stabilizes LDHA through its deubiquitinase activity, resulting in intracellular lactate accumulation. Elevated lactate levels enhance histone lactylation marks, which transcriptionally activate ATP citrate lyase (ACLY) to promote malignant progression via fatty acid synthesis pathway activation. This study reveals a previously unrecognized role of PSMD14-derived lactate in mediating histone lactylation-coupled lipid deposition and tumor progression. Therapeutic co-targeting of PSMD14 and glycolytic lactylation significantly suppresses tumor growth in patient-derived xenograft models, suggesting a promising combinatorial strategy for pancreatic cancer treatment.
    Keywords:  Deubiquitination; LDHA; histone lactylation; lipid metabolism; pancreatic cancer
    DOI:  https://doi.org/10.1002/advs.202505762
  4. Genes Immun. 2025 Oct 04.
    Post-translational acylation modulates immunosuppression and immunotherapy efficacy in hepatocellular carcinoma.
    Yunjie Li, Shuya Bai, Jichang Hu, Heli Li, Chen Hu, Jinzhu Zhao, Hong Qian, Zhouping Tang, Yangyang Feng.
      Acylation modification plays a crucial role in modulating hepatocellular carcinoma (HCC) progression, and their specific prognostic implications in HCC have not been thoroughly investigated. Eleven acylation modifications (crotonylation, lactylation, succinylation, benzoylation, butyrylation, malonylation, glutarylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, palmitoylation, myristoylation, and prenylation) were generated consensus cluster. Then, WGCNA was utilized to identify module genes. Finally, machine learning approach was employed to create acylation modification related genes.score (AMRG.score). This analysis revealed two distinct subtypes of AMRG, each characterized by unique molecular signatures. Through the combination of DEGs, DEGs associated with prognosis, and WGCNA, a total of 21 key genes were identified, leading to the creation of AMRG.score. AMRG.score was rigorously validated across independent external cohorts (TCGA-LIHC, LIRI-JP, GSE10143, GSE14520, GSE27150, GSE36376, and GSE76427) and an in-house cohort, demonstrating its reliability and potential applicability. The AMRG.score serves a dual purpose in its application, as it encapsulates essential the clinical context and offers valuable insights regarding the immunotherapy. In particular, patients categorized with a high AMRG.score displayed an active TME and sensitive to immunotherapy. This novel acylation modification-related prognostic signature could effectively assess the prognosis and therapeutic responses of HCC patients, providing new perspectives for individualized treatment for the patient population.
    DOI:  https://doi.org/10.1038/s41435-025-00362-2
  5. Front Immunol. 2025 ;16 1643112
    ZDHHC5 as a central regulator in a palmitoylation-associated prognostic model for lung adenocarcinoma: insights from pan-cancer and experimental analyses.
    Sixuan Wu, Yuanbin Tang, Junfan Pan, Yaqin Zheng, Qihong Pan, Renji Liang, Haipeng Xu, Jiancheng Li.
       Background: Protein S-palmitoylation is a reversible post-translational modification that plays a significant role in tumor progression. However, the impact of palmitoylation metabolism on the prognosis and tumor microenvironment characteristics of lung adenocarcinoma (LUAD) remains unclear.
    Methods: Clinical and mRNA data from LUAD patients were collected from public databases. A palmitoylation-related gene cluster was constructed using consensus clustering. A prognostic model based on palmitoylation-related genes was developed using univariate Cox regression and Lasso regression analysis, and the contribution of each gene was assessed using shapley additive explanations (SHAP) analysis. The role of the key gene ZDHHC5 in LUAD was experimentally validated.
    Results: Cluster analysis divided patients into two groups, with group B exhibiting a better prognosis. Group A had a higher frequency of TP53 mutations, and significant differences in immune cell infiltration were observed between the two groups. A prognostic risk model, based on five key genes (ZDHHC5, ZDHHC12, ZDHHC21, LYPLA1, and PPT2), revealed significant survival differences between the high-risk and low-risk groups. Immune infiltration analysis showed differences in immune cell lineages and functional activities between risk groups. Drug sensitivity analysis indicated varying patient responses to different chemotherapy drugs across risk strata. Further analysis of ZDHHC5 expression across 33 cancers demonstrated its upregulation in multiple cancers, including LUAD. Experimental results suggest that ZDHHC5 may promote LUAD cell proliferation and metastasis both in vivo and in vitro via the PI3K/AKT pathway.
    Conclusion: A prognostic model based on palmitoylation-related genes offers a valuable tool for survival prediction and the development of personalized treatment strategies in LUAD. ZDHHC5, a key gene related to palmitoylation, demonstrates potential as both a therapeutic target and a prognostic marker for LUAD and other cancers.
    Keywords:  ZDHHC5; immune infiltration; lung adenocarcinoma; palmitoylation; prognostic model
    DOI:  https://doi.org/10.3389/fimmu.2025.1643112
  6. Glycoconj J. 2025 Oct 09.
    Asparagine-linked glycosylation protein 1 (ALG1) promotes aggressive phenotypes of lung adenocarcinoma cells, A549, via modulating N-linked glycosylation and ER-Stress.
    Kanadit Piriyapairoje, Marta Baro, Aanchal Katoch, Bryce De Muth, Ludovica Villanti, Charupong Saengboonmee, Sopit Wongkham, Joseph N Contessa, Chatchai Phoomak.
      Glycosylation plays a critical role in various biological processes and is essential for cell survival. Aberrant glycosylation has been implicated in numerous diseases, including cancer. Lung cancer remains the leading cause of cancer-related mortality worldwide. The correlation between lung cancer progression and abnormal glycosylation has been demonstrated previously. Asparagine-linked glycosylation protein 1 (ALG1) is a key enzyme involved in the N-linked glycosylation process; however, its role in cancer progression remains unclear. In this study, we investigated the function of ALG1 in lung cancer progression. Analysis of the Cancer Genome Atlas (TCGA) dataset revealed that ALG1 expression was significantly upregulated in lung tumor tissues and was associated with poor patient prognosis. To explore its functional relevance, ALG1 expression was depleted in A549 lung adenocarcinoma cells using CRISPR-Cas9-mediated knockout. Loss of ALG1 led to reduced levels of protein N-linked glycosylation and induced an endoplasmic reticulum (ER)-stress response. Functionally, ALG1 knockout significantly impaired A549 cell proliferation, migration, and invasion, as evidenced by phenotypic assays and molecular markers. Moreover, the extent of glycosylation deficiency was positively correlated with ER-stress activation and inversely associated with cancer cell aggressiveness. These findings suggest that ALG1 promotes lung cancer aggressiveness through the regulation of protein glycosylation and modulation of ER-stress pathways. Overall, this study highlights the potential of ALG1 as a therapeutic target and a prognostic biomarker for lung adenocarcinoma patients.
    Keywords:  Asparagine-linked glycosylation 1; Cancer progression; Lung adenocarcinoma; N-glycosylation
    DOI:  https://doi.org/10.1007/s10719-025-10198-7
  7. Front Cell Dev Biol. 2025 ;13 1560491
    Insights into O-GlcNAcylation and programmed cell death in cancer.
    Xiaohan Yan, Wenhao Ren, Zhuang Zhu, Shaoming Li, Rui Shi, Kai Sun, Keqian Zhi, Ling Gao, Jingjing Zheng.
      O-GlcNAcylation is an essential post-translational modification that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to numerous proteins' serine or threonine residues. Several studies have indicated O-GlcNAcylation regulates various processes related to cancer, including signal transduction, transcription, cell division, metabolism, and cytoskeletal regulation. Programmed cell death (PCD) is a regulated and organized form of cell death controlled by genes, including apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis. As research on PCD has become increasingly in-depth, a potential link between O-GlcNAcylation and PCD has emerged. This review will focus on the complex relationships between O-GlcNAcylation and different PCD pathways, which are closely tied to the onset, progression, and resistance of cancer. By clarifying the relationship between O-GlcNAcylation and PCD, we aim to create a theoretical basis for improving anti-cancer treatments, with promising potential for clinical application.
    Keywords:  O-GlcNAcylation; apoptosis; autophagy; cancer; ferroptosis; necroptosis; programmed cell death; pyroptosis
    DOI:  https://doi.org/10.3389/fcell.2025.1560491
  8. Cell Death Dis. 2025 Oct 06. 16(1): 695
    Acetylation-dependent USP7-TRIM25 axis drives oncogenic progression in non-small cell lung cancer.
    Jian Yang, Zhike Chen, Wenxuan Hu, Weibiao Zeng, Zhe Lei, Xin Tong, Qifan Li, Gaomeng Luo, Kang Hu, Zhimeng Chen, Zeyi Liu, Chang Li, Chun Xu, Cheng Ding, Hong-Tao Zhang, Jun Zhao.
      Tripartite motif containing 25 (TRIM25), an E3 ubiquitin ligase that plays an important role in bioprocesses, is frequently elevated in malignant tumors. However, it remains unclear how TRIM25 protein expression is regulated in non-small cell lung cancer (NSCLC). Here, we find that TRIM25 is hyper-expressed in NSCLC tissues and associated with poor prognosis of NSCLC patients. Both in vitro and in vivo experiments indicate that TRIM25 facilitates tumor proliferation and metastasis. Mechanistically, acetylation is identified as a critical post-translational modification (PTM) regulating TRIM25 protein stability in NSCLC. The lysine acetyltransferase cAMP-responsive element-binding (CREB)-binding protein (CBP) mediates acetylation of TRIM25 at lysine 392, which is counteracted by the deacetylase Sirtuin 7 (SIRT7). Notably, the acetylation of TRIM25 enhances its interaction with ubiquitin specific peptidase 7 (USP7), resulting in reduced ubiquitination of TRIM25. In summary, our study reveals a novel acetylation modification site, thus providing new insights into an epigenetic regulation of TRIM25 in human cancer, and suggesting that pharmacological inhibition of TRIM25 acetylation is a potential anti-tumor strategy.
    DOI:  https://doi.org/10.1038/s41419-025-08034-9
  9. Cell Death Differ. 2025 Oct 06.
    O-GlcNAcylation of UGDH regulates its activity and remodels the extracellular matrix to facilitate tumor growth.
    Bingyi Lin, Junjie Zhou, Didi Geng, Siyuan Chai, Xuanming Zhang, Zengle Zhang, Jiating Hu, Qin Tang, Xiaoming Chen, Wen Yi, Liming Wu.
      The tumor microenvironment is an immunosuppressive niche that contributes to tumor growth by downregulating immune cell functions or restraining immune cell infiltration. The underlying mechanisms are not still poorly understood. Here, we demonstrate that O-linked N-acetylglucosamine (O-GlcNAcylation), a prevalent form of protein glycosylation, contributes to establishing the immunosuppressive niche through regulating the metabolic and non-metabolic functions of uridine diphosphate glucose dehydrogenase (UGDH). Tumor cells carrying O-GlcNAcylation-deficient UGDH showed reduced xenograft tumor growth and improved survival in mice. Cytometry by time-of-flight (CyTOF) analysis suggests UGDH O-GlcNAcylation negatively correlates with cytotoxic CD8+ T cell infiltration. O-GlcNAcylation on serine 350 of UGDH is located within the UDP-binding domain, and the subsequent extensive all-atom molecular dynamics simulations reveal that O-GlcNAcylation reinforces hydrogen-bonding interaction and enzymatic activity of UGDH, leading to enhanced hyaluronic acid (HA) synthesis in the extracellular matrix. Moreover, O-GlcNAcylation of UGDH reduces CD8+ T cell infiltration by decreasing the chemokine CXCL10 expression. Specifically, O-GlcNAcylation enhances UGDH interaction with KPNA2 to compete with STAT1, and suppresses translocation of STAT1 into the nucleus, thereby transcriptionally downregulating CXCL10 expression. Thus, our study identifies UGDH O-GlcNAcylation as a key regulator of tumor immunity and further suggests a potential strategy for enhancing immunotherapy.
    DOI:  https://doi.org/10.1038/s41418-025-01591-8
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