bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–10–19
seven papers selected by
Bruna Martins Garcia, CABIMER
  1. Citrullination in tumor immunity and therapy.
  2. Lactylation as a cross-regulatory node in tumor metabolism and epigenetics: insights and therapeutic implications.
  3. Post-translational modifications in hepatocellular carcinoma: mechanisms and therapeutic potential.
  4. S-Palmitoylation regulates signaling mediated by NLRP3 and other innate immune receptors.
  5. FASN inhibits ferroptosis in breast cancer via USP5 palmitoylation-dependent regulation of GPX4 deubiquitination.
  6. Identification of palmitoylation-related lncRNAs as prognostic biomarkers and immune modulators in HCC.
  7. Glycoprotein-Notebook: A pan-cancer glycoproteomic database and toolkit for analysis of protein glycosylation changes associated with cancer phenotypes.
  1. J Clin Invest. 2025 Oct 15. pii: e196348. [Epub ahead of print]135(20):
    Citrullination in tumor immunity and therapy.
    Michael R Pitter, Weiping Zou.
      Peptidyl arginine deiminases (PADs) catalyze the conversion of arginine residues into peptidyl citrulline, a posttranslational modification known as protein citrullination (or arginine deimination). This process alters the charge of proteins from positive to neutral, thereby affecting their folding, stability, conformation, and function. PAD2 and PAD4 can translocate into the nucleus and citrullinate both cytoplasmic and nuclear proteins. In this Review, we focus on PAD2- and PAD4-mediated citrullination in immune cell subsets within the tumor microenvironment. We discuss how citrullination regulates immune cell function and tumor immunity and explore the potential of targeting citrullination as a strategy for cancer immunotherapy.
    DOI:  https://doi.org/10.1172/JCI196348
  2. Front Immunol. 2025 ;16 1675480
    Lactylation as a cross-regulatory node in tumor metabolism and epigenetics: insights and therapeutic implications.
    Zhuangwei Lv, Ruohao Yang, Lulu Liu, Xiaoyu Shi, Ruihan Wang, Jinhua Wu, Junna Jiao.
      Lactylation serves as a pivotal cross-regulatory mechanism linking tumor metabolic reprogramming and epigenetic regulation. This review comprehensively summarizes the mechanisms of lactylation writers, erasers, and readers, highlighting their tumor-specific functions, roles in immunosuppressive tumor microenvironment (TME) remodeling, and contributions to therapeutic resistance. Emerging targeting strategies, including metabolic inhibitors, epigenetic modulators, and combination immunotherapies, exhibit promising preclinical efficacy, highlighting their potential for clinical translation in overcoming therapy resistance and improving cancer immunotherapy.
    Keywords:  Warburg effect; epigenetic regulation; lactylation; metabolic reprogramming; therapeutic
    DOI:  https://doi.org/10.3389/fimmu.2025.1675480
  3. Med Oncol. 2025 Oct 18. 42(11): 524
    Post-translational modifications in hepatocellular carcinoma: mechanisms and therapeutic potential.
    Jianqi Qin, Weixiong Zhu, Zengxi Yang, Shuze Zhang, Wence Zhou.
      Hepatocellular carcinoma (HCC), a prevalent and lethal cancer worldwide, is driven by complex molecular mechanisms. Post-translational modifications (PTMs) crucially influence protein function, stability, and signaling, affecting metabolic reprogramming, cell cycle control, immune evasion, and tumor microenvironment (TME) changes in HCC. Recent studies have increasingly examined various PTMs in HCC, notably phosphorylation, ubiquitination, methylation, glycosylation, acetylation, lactylation, and SUMOylation. These modifications affect key proteins like GPX4, CDK5, PHGDH, GLS1, and HIF-1α, playing roles in cancer development, spread, and treatment resistance. Despite progress, challenges remain in understanding PTMs and applying them clinically. This review aims to summarize recent PTM research in HCC, evaluate their therapeutic potential, and propose strategies for precision therapies in HCC.
    Keywords:  Acetylation; Hepatocellular carcinoma; Phosphorylation; Post-translational modifications; Ubiquitination
    DOI:  https://doi.org/10.1007/s12032-025-03079-4
  4. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00750-6. [Epub ahead of print]85(20): 3862-3873
    S-Palmitoylation regulates signaling mediated by NLRP3 and other innate immune receptors.
    Eugene Varfolomeev, Vishnu Mohanan, Domagoj Vucic.
      The innate immune system coordinates the immediate response to microbial pathogens and tissue damage to allow pathogen clearance and tissue repair. Pathogen recognition receptors (PRRs) recognize danger- and pathogen-associated molecular patterns to trigger immune signaling. The PRR NLRP3 is activated by inflammatory stimuli to instigate the formation of the NLRP3-associated inflammasome. Emerging data highlight the importance of S-palmitoylation (or S-acylation) for NLRP3 activation. Several protein acyltransferases promote NLRP3 S-palmitoylation at a distinct set of cysteine residues to regulate assembly and intracellular localization of the NLRP3 inflammasome. S-Palmitoylation of gasdermin D (GSDMD) and other mediators of innate immunity, including NOD2, Toll-like receptors (TLRs), and stimulator of interferon gene (STING), also modulates immune responses and inflammatory cell death. However, the physiological implication of these S-palmitoylation events has not been established yet, and S-palmitoylation can have a negative effect on inflammatory signaling as well. This review outlines the key features of S-palmitoylation in innate immune signaling and highlights the unresolved questions.
    Keywords:  GSDMD; NLRP3; S-palmitoylation; inflammasome; pyroptosis; zDHHC
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.009
  5. J Exp Clin Cancer Res. 2025 Oct 14. 44(1): 289
    FASN inhibits ferroptosis in breast cancer via USP5 palmitoylation-dependent regulation of GPX4 deubiquitination.
    Zhiwen Qian, Ying Jiang, Yun Cai, Erli Gao, Cenzhu Wang, Jianfeng Dong, Fengxu Wang, Lu Liu, Danping Wu, Feng Zhang, Yida Wang, Xin Ning, Qi Li, Yilan You, Yanfang Gu, Jie Mei, Xinyuan Zhao, Yan Zhang.
      Increasing studies have reported that dysregulated lipid metabolism is an independent risk factor for breast cancer (BC); it would be, therefore, enlightening to investigate the relationship between metabolic reprogramming and the tumor microenvironment in the future. Ferroptosis, a novel form of programmed cell death, is characterized by glutathione (GSH) depletion and inactivation of glutathione peroxidase 4 (GPX4), the central regulator of the antioxidant system. While the close association between fatty acid metabolism and ferroptosis has been studied in various diseases, the interplay between the key fatty acid metabolic enzyme fatty acid synthase (FASN) and ferroptosis in BC remains unexplored. At the beginning of the current study, we demonstrated that FASN expression positively correlates with an immune-cold tumor microenvironment in BC. Subsequent findings revealed that FASN knockdown promotes GPX4 degradation-induced ferroptosis, thereby enhancing the efficacy of anti-programmed cell death protein 1 (PD-1) immunotherapy. Co-immunoprecipitation coupled with mass spectrometry (IP/MS) and co-IP experiments demonstrated that ubiquitin specific protease 5 (USP5) stabilizes GPX4 by binding to and deubiquitinating it. Furthermore, knockdown of FASN inhibited the palmitoylation of USP5, reducing its interaction with GPX4 and consequently increasing GPX4 ubiquitination and degradation. Our results demonstrate that FASN suppresses ferroptosis in BC by stabilizing GPX4 via USP5-mediated mechanisms, highlighting FASN inhibition as a potential therapeutic approach to enhance immunotherapy response.
    Keywords:  Breast cancer; FASN; Ferroptosis; Palmitoylation; USP5
    DOI:  https://doi.org/10.1186/s13046-025-03548-8
  6. Discov Oncol. 2025 Oct 14. 16(1): 1878
    Identification of palmitoylation-related lncRNAs as prognostic biomarkers and immune modulators in HCC.
    Yongkang Zou, Xuejun Zhao, Shengpeng Yang, Yan Liu, Shuaimin Zhang, Xiangang Xu, Gen Chen, Yi Zhang.
      Hepatocellular carcinoma (HCC) has a high mortality rate. Current immunotherapy and targeted treatments have limited effectiveness. Palmitoylation, a reversible lipid modification, is increasingly recognized for its role in tumor progression and immune regulation. However, the function of palmitoylation-related long non-coding RNAs (lncRNAs) in HCC remains unclear. Using The Cancer Genome Atlas (TCGA) data, we identified key palmitoylation-related lncRNAs and developed a prognostic model based on NRAV and AL031985.3. Patients were stratified into high- and low-risk groups. Immune cell infiltration, immune checkpoint gene expression, tumor mutation burden (TMB), and drug sensitivity were analyzed. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to validate lncRNA expression in clinical liver tissue samples from healthy organ donors (normal liver) and HCC patients (tumor tissue). The model effectively distinguished survival differences. High-risk patients exhibited increased Treg cells and immune checkpoint expression, indicating an immunosuppressive phenotype. Functional enrichment analysis revealed associations with cell cycle, immune response, and inflammatory pathways. Combining TMB with the risk score improved prognostic accuracy. Both NRAV and AL031985.3 were significantly up-regulated in tumor tissues compared to normal liver tissues, confirming their diagnostic and prognostic potential. NRAV and AL031985.3 represent promising prognostic biomarkers and immunotherapy targets in HCC. This study provides novel insights into the role of palmitoylation-related lncRNAs in HCC immune regulation.
    Keywords:  Hepatocellular carcinoma; Long non-coding RNA; Palmitoylation
    DOI:  https://doi.org/10.1007/s12672-025-03710-w
  7. Mol Cell Proteomics. 2025 Oct 13. pii: S1535-9476(25)00188-4. [Epub ahead of print] 101089
    Glycoprotein-Notebook: A pan-cancer glycoproteomic database and toolkit for analysis of protein glycosylation changes associated with cancer phenotypes.
    Hui Zhang, Trung Hoang, Yingwei Hu.
      Protein glycosylation plays a pivotal role in various biological processes, and the analysis of intact glycopeptides (IGPs) has emerged as a powerful approach for characterizing alterations in protein glycosylation associated with diseases. Despite the critical insights gained from IGP analysis, dedicated databases, and specialized tools for comprehensive glycoproteomics remain scarce. In response to this deficiency, we developed "Glycoprotein-Notebook", an online resource that consolidates the mass-spectrometry evidence for intact glycopeptides identified from 10 cancer types studied in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) projects and provides analytical tools for in-depth glycopeptide characterization. Using Pancreatic Ductal Adenocarcinoma (PDAC) as a case study, we validated and showcased the toolkit's analytical capabilities. Our results underscore the promise of IGPs as cancer-specific diagnostic and therapeutic targets. Accordingly, Glycoprotein-Notebook emerges as a valuable resource for cancer researchers exploring the intricate relationship between protein glycosylation and cancer phenotypes.
    Keywords:  Cancer; Database; Glycopeptides; Glycoproteomics; Mass spectrometry; Pancreatic Ductal Adenocarcinoma (PDAC)
    DOI:  https://doi.org/10.1016/j.mcpro.2025.101089
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