bims-prolim 2025-06-22 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–06–22
eleven papers selected by
Bruna Martins Garcia, CABIMER

Recent Overview of Protein Palmitoylation and Profiling Methodologies.
Navigating the role of protein lactylation in prostate cancer and its implications for immunotherapy.
Protein lactylation and immunotherapy in gliomas: A novel regulatory axis in tumor metabolism (Review).
Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.
Lipid Modification and Membrane Localization of Proteins in Cell-Free System.
Protein acylations in cancer immunity: effects and therapeutic opportunities.
Palmitoylation-driven immune dysregulation and prognostic signature in low-grade glioma: a multi-omics and functional validation study.
NDRG1-Driven Lactate Accumulation Promotes Lung Adenocarcinoma Progression Through the Induction of an Immunosuppressive Microenvironment.
Posttranslational remodeling micelle reverses cell-surface and exosomal PD-L1 immunosuppression in tumors resistant to PD-L1 antibody therapy.
YEATS2 O-GlcNAcylation Promotes Chromatin Association of the ATAC Complex and Lung Cancer Tumorigenesis.
Protocol for the visualization and identification of S-palmitoylated proteins in HCT-116 cells using metabolic labeling via click chemistry.

Methods Mol Biol. 2025 ;2921 361-370

Recent Overview of Protein Palmitoylation and Profiling Methodologies.

Changyan Jin, Qiaoling Yuan, Zhipeng Tao.

  Protein palmitoylation is a reversible posttranslational modification in which a palmitoyl group (a 16-carbon saturated fatty acid) is covalently attached to cysteine residues on proteins, typically through a thioester bond. This modification affects the protein's hydrophobicity, influencing its membrane association, localization, stability, trafficking, and overall function. Dysregulation of palmitoylation has been implicated in diseases such as cancer, neurodegenerative diseases, and cardiovascular disorders. In this review, we summarize the recent findings related to protein palmitoylation and its biological functions. More importantly, we examine proteomic studies that utilize active-based protein profiling (ABPP) to design novel probes or inhibitors aimed at enhancing the accuracy and efficiency of large-scale analyses of protein palmitoylation. These advancements will facilitate the findings of novel therapeutic targets and the designing of targeted therapies, providing increasingly critical insights into the role of this modification in health and diseases.

Keywords:  Active-based protein profiling; Chemical probes; Palmitoylation

DOI:  https://doi.org/10.1007/978-1-0716-4502-4_20
J Cancer. 2025 ;16(8): 2706-2719

Navigating the role of protein lactylation in prostate cancer and its implications for immunotherapy.

Dongzhang Li, Kaifeng Wang, Guantao Lou, Wangjian Li, Quan Ma, Yu'e Liu, Yongliang Chen.

  Prostate cancer is an aggressive malignancy with high prevalence and significant mortality, characterized by its remarkable metabolic adaptability and immune complexity. Emerging evidence has highlighted the critical role of post-translational modifications (PTMs) in cancer biology, with protein lactylation gaining attention as a novel PTM with profound implications. Lactylation, derived from lactate, links the altered metabolic processes of tumor cells to diverse cellular functions, including epigenetic regulation and protein dynamics. It significantly influences tumor progression, immune evasion, and therapeutic resistance by modulating key immune cells within the tumor microenvironment. The immunosuppressive conditions created by lactate and lactylation favor tumor survival in prostate cancer. Thus, targeting lactylation offers innovative strategies for treating prostate cancer. By leveraging lactylation modulation, particularly in combination with immune checkpoint inhibitors, there is potential to enhance anti-tumor immune responses and improve treatment outcomes. This review explores the intersection of metabolic alterations and immune modulation, underscoring lactylation as a promising therapeutic avenue in prostate cancer.

Keywords:  immune checkpoints; immunotherapy; lactylation; prostate cancer; tumor microenvironment

DOI:  https://doi.org/10.7150/jca.114137
Int J Oncol. 2025 Jul;pii: 58. [Epub ahead of print]67(1):

Protein lactylation and immunotherapy in gliomas: A novel regulatory axis in tumor metabolism (Review).

Tao Luo, Liang Liu, Hao Wang, Shuai Wen.

  Gliomas are the most common primary brain tumors, and exhibit highly heterogeneous and aggressive biological behaviors. Metabolic reprogramming is a hallmark of gliomas, and lactate accumulation serves a critical role in tumor progression. In addition to its traditional role as a metabolic byproduct, lactate has been recognized as a signaling molecule that modifies proteins through lactylation, which is a novel post‑translational modification. Lactate‑induced lactylation of histone and non‑histone proteins is emerging as a key epigenetic and metabolic regulator that influences glioma development, immune evasion, angiogenesis and therapeutic resistance. The present review provides mechanistic insights into protein lactylation, its role in glioma progression and its potential therapeutic implications. Targeting lactate metabolism and lactylation‑modifying enzymes holds promise for improving glioma treatment outcomes.

Keywords:  PTM; gliomas; immunotherapy; lactylation; metabolism; therapy

DOI:  https://doi.org/10.3892/ijo.2025.5764
Biochim Biophys Acta Rev Cancer. 2025 Jun 11. pii: S0304-419X(25)00115-5. [Epub ahead of print]1880(4): 189373

Lactate metabolism reprogramming in PDAC: Potential for tumor therapy.

Fan Gao, Kang Sun, Sicheng Wang, Xiaozhen Zhang, Xueli Bai.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. During tumor progression, metabolic reprogramming plays a crucial role in both tumor proliferation and immune evasion. In PDAC, genetic mutations and environment limitations lead to resulting in increased lactate production through enhanced glycolysis. Elevated glycolysis is a significant metabolic feature in pancreatic cancer, leading to lactate accumulation within both the tumor cells and tumor immune microenvironment. Lactate not only promotes tumor growth and sustains its survival but also has a profound impact on the immune-suppressive phenotype switch of immune cells. Lactate promotes tumor progression through various biological processes. Pharmacological agents targeting lactate generation, accumulation and lactate-related molecular pathways show potential clinical translation value in cancer treatment.

Keywords:  GPR81; Lactate metabolism; Lactylation; Metabolic reprogramming; PDAC; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2025.189373
ACS Synth Biol. 2025 Jun 19.

Lipid Modification and Membrane Localization of Proteins in Cell-Free System.

Rena Matsumoto, Tatsuya Niwa, Kaori Kuno, Yasuhiro Shimane, Yutetsu Kuruma, Takashi Kanamori.

  Post-translational modifications are an essential process for proper protein function and localization. In particular, lipid modification plays a crucial role in the spatial regulation of proteins functioning on a lipid membrane surface. While cell-free protein synthesis allows rapid protein production, technical advances in lipidation modification are behind. Here, we developed a cell-free system for the myristoylation and palmitoylation of proteins. Based on our previous study, we improved myristoylation efficiency by trimming a precursor nascent peptide, which undergoes lipidation at the N-terminal glycine. We also found that N-myristoyltransferase (NMT) catalyzes both myristoylation and palmitoylation. The localization of lipidated proteins onto liposomes is further aided by the insertion of polyarginine residues downstream of the NMT recognition site. Finally, we demonstrated that lipidation of VHH antibodies and localization onto liposomes resulted in target-specific binding to cancer cells. This system offers a platform for displaying soluble proteins on lipid membranes, with potential applications in developing liposomes for targeted cell binding.

Keywords:  PURE system; VHH antibody; cell-free protein synthesis; lipid modification; liposomes

DOI:  https://doi.org/10.1021/acssynbio.5c00155
Trends Pharmacol Sci. 2025 Jun 19. pii: S0165-6147(25)00101-4. [Epub ahead of print]

Protein acylations in cancer immunity: effects and therapeutic opportunities.

Jia-Cheng Lai, Yi-Ting Jiang, Shougeng Liu, Simeng Wang, Wei Cui, Lihui Wang.

  Acylations are conserved and dynamic modifications that control various biological processes, including gene transcription and protein biology, and have been tied to diseases, such as cancers. Due to their reversible characteristic, acylations exhibit great therapeutic potential through targeting of their regulatory enzymes and proteins. Recent studies have improved our understanding of the close interplay between acylations and the tumor immune microenvironment (TIME), showing the potential to improve antitumor immune responses via acylation manipulation. Herein, we review the effects of acylations, including acetylation, lactylation, palmitoylation, and some less well-known acylations on cancer immunity, and corresponding therapeutic opportunities. Specifically, we bring into focus diverse roles of different acylation-related enzymes, metabolites, or substrates to provide insights into targeting acylations to increase antitumor immunity and generate broader research enthusiasm.

Keywords:  acylation; epigenetics; immune escape; immunotherapy; post-translational modifications; tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.tips.2025.05.011
Front Pharmacol. 2025 ;16 1586921

Palmitoylation-driven immune dysregulation and prognostic signature in low-grade glioma: a multi-omics and functional validation study.

Zehao Wang, Tianlun Yu, Yuqiao Liu, Yufan Wu, Jingqing Hu.

   Background: Palmitoylation, a critical post-translational modification, regulates protein localization and function in cancer. However, its role in glioma progression, immune modulation, and prognosis remains poorly understood.
Methods: We integrated transcriptomic, clinical, and mutation data from multicenter cohorts to analyze 30 palmitoylation-related genes in low-grade gliomas (LGG). Consensus clustering, differential expression analysis, and LASSO regression were employed to define palmitoylation clusters, identify prognostic genes, and construct a risk signature. The evaluation of immune infiltration and immunotherapy efficacy was further conducted across different risk groups. In the palmitoylation-related risk model, IGFBP2 was functionally validated through siRNA-mediated knockdown and a series of assays, including EdU incorporation, cell cycle analysis, wound healing, and transwell migration assays.
Results: Two palmitoylation clusters (A/B) were identified, with Cluster B exhibiting poorer survival (P < 0.001), enriched JAK-STAT signaling, and elevated immune infiltration (M1/M2 macrophages, CD8+ T cells). A five-gene prognostic signature (CHI3L1, IGFBP2, MEOX2, EMILIN3, SFRP2) demonstrated robust predictive accuracy in training (AUC 0.92-0.94) and validation cohorts (AUC 0.68-0.83). High-risk patients showed upregulated PD-1, PD-L1, and CTLA4 (P < 0.001) and higher TIDE scores, indicative of immune dysfunction. IGFBP2 knockdown suppressed glioma cell proliferation (P < 0.01) and migration (P < 0.001), linking it to tumor aggressiveness.
Conclusion: Palmitoylation plays a pivotal role in LGG progression by influencing immune evasion and stromal interactions. The developed prognostic signature and nomogram offer practical tools for risk stratification in clinical settings, with IGFBP2 identified as a promising therapeutic target. These insights highlight the potential of palmitoylation-focused therapies to enhance outcomes for LGG patients.

Keywords:  IGFBP2; LGG; immune infiltration; immunotherapy; palmitoylation; prognostic signature; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2025.1586921
Adv Sci (Weinh). 2025 Jun 20. e01238

NDRG1-Driven Lactate Accumulation Promotes Lung Adenocarcinoma Progression Through the Induction of an Immunosuppressive Microenvironment.

Gujie Wu, Hongxia Cheng, Jiacheng Yin, Yuansheng Zheng, Haochun Shi, Binyang Pan, Ming Li, Mengnan Zhao, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Guoshu Bi, Weigang Guo, Lin Wang, Yiwei Huang.

  Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, with the tumor microenvironment (TME) playing a critical role in its progression. Metabolic reprogramming, particularly lactate accumulation, drives immune suppression within the TME. Utilizing single-cell RNA sequencing (scRNA-seq) of 30 LUAD samples, genome-wide association studies (GWAS) involving 29,863 patients and 55,586 controls, and clinical data from 220 LUAD patients, we identified N-Myc downstream-regulated gene 1 (NDRG1) as a key pathogenic gene in LUAD, strongly associated with tumor progression and poor prognosis. Mechanistic studies revealed that NDRG1 stabilizes lactate dehydrogenase A (LDHA) by inhibiting its ubiquitination, thereby enhancing glycolysis and promoting lactate accumulation. This process fosters immune suppression by inducing M2 macrophage polarization, impairing CD8+ T cell function, and upregulating immunosuppressive genes. Furthermore, histone H3K18 lactylation in macrophages exacerbates this immunosuppressive state. Clinically, elevated NDRG1 expression correlates with increased PD-L1 levels, a higher abundance of immunosuppressive macrophages, and reduced CD8+ T cell infiltration, contributing to immunotherapy resistance. Conversely, low NDRG1 expression is associated with enhanced CD8+ T cell infiltration and improved therapeutic outcomes. Preclinical studies demonstrated targeting NDRG1 suppresses tumor growth, alleviates immune suppression, and boosts anti-PD-L1 efficacy. These findings establish NDRG1 as a critical LUAD regulator and a promising immunotherapy target.

Keywords:  NDRG1; immunotherapy; lactylation; lung adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.202501238
J Control Release. 2025 Jun 14. pii: S0168-3659(25)00581-4. [Epub ahead of print]384 113961

Posttranslational remodeling micelle reverses cell-surface and exosomal PD-L1 immunosuppression in tumors resistant to PD-L1 antibody therapy.

Xue Shi, Xiejun Zhao, Yinli He, Linpei Zhang, Xinmin Zheng, Xiangchuan Qin, Kefeng Li, Jing Li, Yawen Wang, Liangliang Dai, Xiaojiao Li.

  Sustained replenishment of cell-surface and exosomal PD-L1 has been believed as the most important factor in the progression of PD-L1 antibody therapy resistance. Given that direct genetic blockade of PD-L1 may lead to unintended consequences and that posttranslational modifications (PTMs) are often used as pharmacological targets of cancer therapy, approaches targeting PD-L1 PTMs show great potential as new therapeutic paradigms. Palmitoylation has emerged as a critical PTM for modulating PD-L1 stability and distribution. In this work, it is found that disruption of palmitoylation by 2-bromopalmitate (2-BP) dual-impaired PD-L1 on the cell surface and exosomes. An amphiphilic TME-responsive micelle was fabricated to efficiently deliver 2-BP and the chemotherapeutic agent cisplatin to tumor milieu. The composite formulation unifying elimination of cell-surface and exosomal PD-L1 with chemotherapy synergistically relieved immunosuppression in the tumor bed and draining lymph node, thereby dramatically restraining growth, postsurgical relapse, and metastasis in melanoma resistant to PD-L1 antibody therapy. Moreover, the formulation elicits potent T cell memory responses for long-term protection against tumor rechallenge. In summary, our study takes advantage of an amphiphilic nanoformula combination of a posttranslational modifier and chemotherapy to target tumors resistant to PD-L1 antibody therapy, and paves a new path for multimodal cancer treatment.

Keywords:  Cell-surface PD-L1; Exosomal PD-L1; Immunosuppression; Palmitoylation; Posttranslational remodeling micelle

DOI:  https://doi.org/10.1016/j.jconrel.2025.113961
J Biol Chem. 2025 Jun 18. pii: S0021-9258(25)02238-0. [Epub ahead of print] 110388

YEATS2 O-GlcNAcylation Promotes Chromatin Association of the ATAC Complex and Lung Cancer Tumorigenesis.

Jianxin Zhao, Zheng Zhao, Wen Zhou, Jianzhi Zhang, Jinfeng Chen, Jianwei Sun, Jing Li.

  The intracellular O-linked N-acetylglucosamine (O-GlcNAc) modification is known to be enriched in the nucleus and on chromatin, but many of its chromatin targets remain to be identified. Herein we demonstrate the O-GlcNAcylation of YEATS Domain Containing 2 (YEATS2), a subunit of the chromatin Ada-two-A-containing (ATAC) complex and a reader of histone H3K27ac. We show that YEATS2 interacts with the O-GlcNAc transferase (OGT) and further pinpoint its major O-GlcNAcylation site to be Thr604 using electron transfer dissociation mass spectrometry. O-GlcNAcylation promotes the chromatin association of YEATS2, and the affinity between YEATS2 and other ATAC components on chromatin, such as ZZZ3, GCN5 and PCAF. Downstream, YEATS2-T604A mutants attenuated the ATAC-dependent histone H3K9ac levels and inactivated the expression of essential ribosomal genes as shown in chromatin immunoprecipitation assays. Further, xenograft experiments show that YEATS2 O-GlcNAcylation promotes lung cancer tumorigenesis. Our work reveals the critical role of YEATS2 O-GlcNAcylation in stabilizing the ATAC complex on chromatin and expands the chromatin substrates of OGT.

Keywords:  ATAC; H3K9ac; O-GlcNAc; YEATS2; ZZZ3

DOI:  https://doi.org/10.1016/j.jbc.2025.110388
STAR Protoc. 2025 Jun 12. pii: S2666-1667(25)00296-5. [Epub ahead of print]6(2): 103890

Protocol for the visualization and identification of S-palmitoylated proteins in HCT-116 cells using metabolic labeling via click chemistry.

Nadine Merz, Sabine Grösch.

  Reversible S-palmitoylation facilitates the regulation of a plethora of protein functions. Here, we present a protocol for enriching lipidated proteins with click-chemistry labeling and immunoprecipitation using biotin-azide-streptavidin interaction where protein activity assays are possible. We describe steps for performing the copper-based reaction for high-scale applications in milligram ranges, sample preparation, and the elution of palmitoylated-biotinylated proteins. Further, we detail procedures for the quantification of S-palmitoylation of isolated membrane proteins via reporter fluorophore on the western-blot level without lipid background. For complete details on the use and execution of this protocol, please refer to Merz et al.1.

Keywords:  Cell Membrane; Cell culture; Organoids

DOI:  https://doi.org/10.1016/j.xpro.2025.103890