bims-prolim 2025-07-06 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–07–06
twelve papers selected by
Bruna Martins Garcia, CABIMER

Pharmacologically targeting protein lactylation to overcome cancer drug resistance.
Lactylation in tumor: mechanisms and therapeutic potentials.
Histone lactylation as a driver of metabolic reprogramming and immune evasion.
Exploring lactylation and cancer biology: insights from pathogenesis to clinical applications.
Quantitative Proteomics Reveals the Role of Lysine Lactylation in Lenalidomide-Resistance in Multiple Myeloma Cells.
Straight A's: protein acylation in the S-activation and autophagic degradation of NOD-like receptors.
Single-cell sequencing has revealed the palmitoylation landscape in lung adenocarcinoma and identified ABHD17C as a novel biomarker.
ZDHHC14 and APT2 regulate the palmitoylation of HSV-2 gB.
Exploring the role of protein palmitoylation in cancer progression and therapy: a comprehensive bibliometric study (2004-2024).
PD-L1 delactylation-promoted nuclear translocation accelerates liver cancer growth through elevating SQLE transcription activity.
CLDN4 palmitoylation promotes hepatic-to-biliary lineage transition and lenvatinib resistance in hepatocellular carcinoma.
Targeting O-GlcNAcylation in Tumor-Associated Inflammation: From Molecular Mechanisms to Cancer Therapy.

Eur J Med Chem. 2025 Jun 26. pii: S0223-5234(25)00670-1. [Epub ahead of print]296 117905

Pharmacologically targeting protein lactylation to overcome cancer drug resistance.

Yumin Wang, Jinxia Chen, Yan Wang, Jun Zhao, Junjing Zhang, Hongquan Wang.

  Drug resistance remains a major challenge in cancer therapy. Emerging evidence has revealed that protein lactylation, a newly discovered post-translational modification of lysine residues in histone and non-histone proteins, contributes to drug resistance in cancers. In this review, we aimed to provide an overview of the newly identified lactylation regulators (lactylation writers, erasers, and readers) and their roles and summarize the recent advances in the mechanisms by which lactylation modulates cancer drug resistance to highlight the role of lactylation in mediating cancer cell resistance to chemotherapy, immunotherapy, and targeted cancer therapy. We also aimed to provide an overview of the recent findings and emerging concepts that leverage lactylation through pharmacological inhibition to overcome drug resistance in cancers.

Keywords:  Cancer; Drug resistance; Lactylation; Lactylation regulators

DOI:  https://doi.org/10.1016/j.ejmech.2025.117905
Front Immunol. 2025 ;16 1609596

Lactylation in tumor: mechanisms and therapeutic potentials.

Dandan Wang, Hao Rong, Ke Ma, Jun Peng.

  Lactate, a central product of glucose metabolism, plays a vital role in energy supply and signal transduction, and it also participates in gene transcription regulation through lactylation. Metabolic reprogramming is a key feature of tumor cells and highlights the important role of lactylation in cancer development. Recent studies have emphasized the significant regulatory roles of lactylation in cancer, suggesting that it may serve as a potential target for treatment. This review discusses the mechanisms, regulation, and functions of lactylation in cancer. It also explores the possible significance of lactylation as a marker for the diagnosis and therapy of tumor, and evaluates the therapeutic prospects of targeting lactylation. While the precise mechanisms of lactylation in cancer regulation require further investigation, its significant influence indicates promising avenues for future research.

Keywords:  lactate; lactylation; post-translational modifications; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1609596
Med Rev (2021). 2025 Jun;5(3): 256-259

Histone lactylation as a driver of metabolic reprogramming and immune evasion.

Qiaoting Cai, Wei Deng, Yutian Zou, Zhe-Sheng Chen, Hailin Tang.

  Lactate is the end product of glycolysis, and extensive research has shown that lactate participates in various pathophysiological processes. Along with associated hydrogen ions, lactate typically functions as an immunosuppressive negative factor and plays a crucial role in tumor metabolic reprogramming. The recently discovered lactylation is a novel epigenetic modification that, similar to other epigenetic modifications, modifies histones to alter chromatin spatial configuration, thereby affecting DNA accessibility and regulating gene expression. More importantly, the degree of lactylation is closely related to local lactate concentrations, establishing a link between epigenetics and metabolic reprogramming. During cellular metabolism, lactate accumulation promotes histone lysine lactylation in cancer cells and immune cells such as macrophages and T cells, playing an essential role in tumor immune evasion and resistance to immunotherapy. This paper details the role of lactylation modifications in cancer immune evasion and resistance to immunotherapy, providing novel therapeutic directions and targets for cancer treatment.

Keywords:  cancer; histone lactylation; immune escape; immunotherapy resistance

DOI:  https://doi.org/10.1515/mr-2024-0091
Front Cell Dev Biol. 2025 ;13 1598232

Exploring lactylation and cancer biology: insights from pathogenesis to clinical applications.

Zixuan Gou, Qianchuang Sun, Jiannan Li.

  As a byproduct of glycolysis, lactate functions as a signaling molecule, a substrate for energy metabolism, and a regulator of the tumor microenvironment (TME). It is involved in various biological processes, including energy shuttling, tumor growth and invasion, drug resistance, and immune evasion. Lactylation, a recently identified post-translational modification (PTM), acts as a bridge between gene regulation and cellular metabolism, thus playing a crucial role in tumor biology. Similar to other epigenetic modifications, lactylation influences the spatial conformation of chromatin, modulates DNA accessibility, and regulates gene expression. It intricately participates in TME-related processes by orchestrating immune state transitions and enhancing the malignant characteristics of tumors. This review summarizes lactylation-related genes in tumors, the role of lactylation in the TME, the interactions of the genes with other metabolic pathways, and the potential mechanisms underlying tumor progression as well as their clinical implications. Despite its nascent stage, research on the epigenetic regulation of tumor-related genes by lactylation holds promise. In this review, we highlighted unresolved challenges in this field and provided insights that may guide the development of novel targeted therapies for cancer.

Keywords:  lactylation; post-translational modification; prognostic biomarkers; therapeutic target; tumor progression

DOI:  https://doi.org/10.3389/fcell.2025.1598232
ACS Chem Biol. 2025 Jul 01.

Quantitative Proteomics Reveals the Role of Lysine Lactylation in Lenalidomide-Resistance in Multiple Myeloma Cells.

Xinlong Guo, Xuelian Ren, Cong Yan, He Huang.

Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal plasma cell proliferation, with lenalidomide emerging as a primary treatment. However, prolonged use often leads to drug resistance, underscoring the need to understand the resistance mechanisms. Protein post-translational modifications (PTMs) play crucial roles in disease development, including chemoresistance. Here, we investigate the involvement of new types of PTMs, focusing on lysine lactylation (Kla), in lenalidomide-resistance. Glycolysis-driven elevation of Kla levels was observed in lenalidomide-resistant MM cells, and the subsequent inhibition of glycolytic activity significantly reversed the lenalidomide-resistance phenotype. Through quantitative proteome, lactylome, and acetylome analyses, we identified 7493 proteins, 1241 Kla sites, and 9313 lysine acetylation (Kac) sites, thereby revealing differential protein expression and PTM profiles in lenalidomide-resistant cells. Proteomic analysis revealed that a series of chemoresistance-related proteins were upregulated, and a number of Cullin-RING Ligase 4-Cereblon (CRL4CRBN) regulatory factors were downregulated. Lactylome analysis revealed that numerous chemoresistance-related proteins exhibited increased Kla levels in lenalidomide-resistant MM cells, suggesting that Kla played an important role in the development of lenalidomide-resistance in LenR MM cells. Notably, histone H4K8la was associated with upregulation of chemoresistance-related genes cyclin-dependent kinase 6 (CDK6) and enoyl-CoA hydratase (ECHS1). Our findings shed light on the epigenetic mechanisms underlying lenalidomide-resistance in MM, offering insights for overcoming chemoresistance.

DOI: https://doi.org/10.1021/acschembio.5c00270
Biochem Soc Trans. 2025 Jul 04. pii: BST20253026. [Epub ahead of print]

Straight A's: protein acylation in the S-activation and autophagic degradation of NOD-like receptors.

Noah R Martin, Gregory D Fairn.

  Over the past decade, S-acylation has emerged as a crucial regulator of several innate immune signaling pathways, with new insights continually being gained. S-acylation, a reversible post-translational modification, involves the attachment of fatty acyl chains to cysteine residues, influencing protein localization, function, and stability. In this mini-review, we examine the accumulating evidence of the role of S-acylation in regulating nucleotide oligomerization domain (NOD)-like receptors. NOD-like receptor subfamily P3 (NLRP3), a key player in inflammasome formation, undergoes S-acylation at specific cysteine residues, which are essential for its localization to the trans-Golgi network and other organelles. Various zinc finger Asp-His-His-Cys motif-containing (zDHHC) enzymes mediate this modification, with zDHHC5 being particularly important for activation and the ability of NLRP3 to interact with never in mitosis gene A (NIMA)-related protein kinase 7 (NEK7), promoting inflammasome assembly, caspase-1 activation, and pyroptosis. Alternatively, S-acylation by zDHHC12 targets NLRP3 for chaperone-mediated autophagy, preventing excessive inflammation. NOD2, another NLR, requires S-acylation for membrane localization and effective signaling via the NF-κB and mitogen-activated protein kinase pathways in response to peptidoglycan components. Dysregulation of S-acylation in NOD2 is associated with Crohn's Disease (hypo-acylated) and Blau syndrome/early-onset sarcoidosis (hyper-acylated). Soluble NOD2 lacking S-acylation is ubiquitinated and eliminated by the autophagic pathway. This review highlights the significance of understanding the S-acylation cycle and its regulatory mechanisms in developing potential therapeutic interventions for related inflammatory diseases. We also discuss unresolved questions regarding the S-acylation of NOD2 and NLRP3, as well as the regulation of S-acylation in general.

Keywords:   S-acylation; NF-κB; NLRP3; NOD2; ZDHHC; inflammation

DOI:  https://doi.org/10.1042/BST20253026
Am J Pathol. 2025 Jun 27. pii: S0002-9440(25)00210-X. [Epub ahead of print]

Single-cell sequencing has revealed the palmitoylation landscape in lung adenocarcinoma and identified ABHD17C as a novel biomarker.

Benliang Wei, Anhong Li, Guofa Zhao, Rongfang Liu, Peng Liu, Xu Zhang, Fangchao Zhao, Shujun Li, Xinyue Zhang, Xuguang Zhang.

Protein S-palmitoylation, a reversible posttranslational modification, is crucial for tumor progression. However, the palmitoylation landscape in tumor cells and its variability within different tumor cell populations remain underexplored. We analyzed protein palmitoylation using 23 palmitoyl-acyltransferases and seven de-palmitoyl-acyltransferases. Through copy-number variation, pseudotime, enrichment, and cell-cell communication analyses, we explored heterogeneity among epithelial cells in LUAD. Palmitoylation levels are elevated in normal epithelial cells, while de-palmitoylation predominates in tumor-derived cells. As clinical stage advances, palmitoylation declines and de-palmitoylation increases. We identified a C4 epithelial subtype associated with epithelial-to-mesenchymal transition and angiogenesis, marked by low palmitoylation and high de-palmitoylation. This subtype, located at the end of the tumorigenic trajectory, shows intense communication with fibroblasts and endothelial cells but minimal interaction with immune cells, indicating enhanced invasiveness and immune evasion. ABHD17C, a key marker of the C4 subtype, was found to regulate tumor cell proliferation, and its knockdown reduced growth and increased apoptosis. We identified a C4 epithelial subtype linked to LUAD metastasis and highlighted ABHD17C as a potential biomarker and therapeutic target.

DOI: https://doi.org/10.1016/j.ajpath.2025.05.024
Virology. 2025 Jun 25. pii: S0042-6822(25)00227-2. [Epub ahead of print]610 110614

ZDHHC14 and APT2 regulate the palmitoylation of HSV-2 gB.

Yajie Chen, Guangfu Yu, Shan Gao, Leiliang Zhang.

  Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted pathogen known for causing genital herpes. Glycoprotein B (gB) of HSV-2 plays a crucial role in viral entry and infection. However, its post-translational modifications are not well understood. This study investigated the palmitoylation of HSV-2 gB, identifying cysteine residue 8 (C8) as a critical palmitoylation site. Using an acyl-biotin exchange assay, we confirmed that gB was indeed palmitoylated, and treatment with 2-bromopalmitate significantly reduced this modification. Further analysis revealed that ZDHHC14 interacted with gB and facilitated its palmitoylation. We also identified APT2 as a negative regulator of gB palmitoylation. Importantly, palmitoylation enhanced gB's localization to the plasma membrane, whereas the C8S mutation substantially impaired this localization. Functionally, palmitoylation of gB enhanced the infective efficiency of HSV-2 pseudotyped particles (pp) and live viruses, while both palmitoyltransferase and APT2 inhibition affected the entry efficiency of HSV-2pp. Our findings demonstrate that the palmitoylation of gB is crucial for its localization to the membrane and for facilitating efficient HSV-2 infection, highlighting palmitoylation as a promising target for antiviral interventions and providing new insights into the pathogenesis of HSV-2.

Keywords:  APT2; HSV-2; Palmitoylation; ZDHHC14; gB

DOI:  https://doi.org/10.1016/j.virol.2025.110614
Discov Oncol. 2025 Jul 01. 16(1): 1221

Exploring the role of protein palmitoylation in cancer progression and therapy: a comprehensive bibliometric study (2004-2024).

Yu Chen, Yuxuan Dai, Xing Wang, Jian Liu.

   OBJECTIVE: This study aims to qualitatively and quantitatively assess the research landscape of palmitoylation in oncology using bibliometric analysis, thereby providing insights into research hotspots and emerging trends.
METHODS: The data were sourced from the Web of Science Core Collection, retrieved using predefined search terms, and comprise review articles and original research papers published in English from 2004 to 2024. Bibliometric analysis and data visualization were performed using VOSviewer, CiteSpace, and Microsoft Excel.
RESULTS: The United States and China are the leading contributors to research in this field, with Shanghai Jiao Tong University being the most prolific institution in terms of publication output. Current research hotspots in protein palmitoylation related to oncology primarily encompass the enzymatic mechanisms and dynamic regulation of palmitoylation, palmitoylation-mediated lipid metabolic reprogramming and tumorigenesis, palmitoylation-mediated tumor signaling pathways, and targeted cancer therapy strategies based on palmitoylation modification. Current research trends primarily focus on the modulation of critical enzymes and signaling pathways, which influence tumor biology and prognosis. Additionally, emphasis is placed on metabolic reprogramming mediated by protein palmitoylation within the tumor microenvironment, especially regarding its role in tumor responsiveness to chemotherapy and immunotherapy.
CONCLUSION: This study provides a comprehensive overview of recent advancements in research regarding protein palmitoylation modifications within oncology.

Keywords:  Bibliometrics; Cancer; Immunotherapy; Metabolic reprogramming; Palmitoylation

DOI:  https://doi.org/10.1007/s12672-025-03059-0
Cancer Lett. 2025 Jul 02. pii: S0304-3835(25)00469-0. [Epub ahead of print] 217901

PD-L1 delactylation-promoted nuclear translocation accelerates liver cancer growth through elevating SQLE transcription activity.

Xue Wang, Ye Li, Yanxin Tang, Zhiyu Liu, Yuan Liu, Xueli Fu, Shiman Guo, Jiaqi Ma, Fangyuan Ma, Zhitu Zhu, Weiying Zhang, Lihong Ye.

  Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is overexpressed in several malignancies. The newly identified protein posttranslational modification lactylation, occurring on lysine residues, is extensively involved in various biological processes. However, PD-L1 lactylation and its role in tumorigenesis remain unclear. In this study, we discover that lactylation of PD-L1 suppresses liver cancer growth by inhibiting cholesterol synthesis. Acetyltransferase E1A-binding protein p300 (p300) catalyzes the lactylation of PD-L1 at the lysine 189 residue (K189). Histone deacetylase 2-dependent delactylation of PD-L1 K189 promotes vimentin-mediated nuclear translocation of PD-L1. Functionally, PD-L1 K189 delactylation accelerates liver cancer growth both in vitro and in vivo by facilitating cholesterol production. Clinically, an antibody against PD-L1 K189 lactylation reveals that PD-L1 delactylation is positively associated with the progression of liver cancer histological grade. Mechanistically, PD-L1 K189 delactylation upregulates SQLE, a rate-limiting enzyme in cholesterol biosynthesis, by increasing SQLE transcription activity via the transcription factor YY1. Therefore, our findings demonstrate that lactylation-dependent regulation of PD-L1 promotes liver cancer growth.

Keywords:  Cholesterol biosynthesis; Lactylation; Liver cancer; Nuclear translocation; PD-L1

DOI:  https://doi.org/10.1016/j.canlet.2025.217901
Cell Rep Med. 2025 Jun 24. pii: S2666-3791(25)00281-2. [Epub ahead of print] 102208

CLDN4 palmitoylation promotes hepatic-to-biliary lineage transition and lenvatinib resistance in hepatocellular carcinoma.

Minghao Xu, Yimin Zheng, Junbo Chen, Chao Gao, Miao Zhu, Aying Ma, Bugang Liang, Wenxin Xu, Jia Fan, Haibo Zhou, Aiwu Ke, Yinghao Shen.

  Hepatocellular carcinoma (HCC) exhibits significant plasticity, enabling phenotypic switching that promotes a drug-tolerant state and circumvents drug-induced cytotoxicity. In this study, we identify the hepatic-to-biliary lineage transition (HBT), associated with Claudin 4 (CLDN4), a tight junction protein, as a potential target for mitigating lenvatinib resistance in HCC. CLDN4 expression is more prevalent in lenvatinib-resistant patients. Palmitoylation of CLDN4 at cysteine residues C104 and C107 regulates ubiquitination at lysine residue K103, inhibits clathrin-mediated endocytosis, and sustains CLDN4 anchoring within lipid rafts. Anchored CLDN4 facilitates the phenotypic transition of HCC cells, resulting in increased resistance to lenvatinib by driving the mobilization of contactin-1 to lipid rafts and activating the Notch signaling pathway. Salvianolic acid B, an inhibitor of CLDN4, is demonstrated to reduce both HBT and lenvatinib resistance in HCC. Additionally, combination chemotherapy appears to be an effective therapeutic strategy for HCC patients undergoing HBT.

Keywords:  Claudin4; hepatic-to-biliary transition; hepatocellular carcinoma; lenvatinib resistance; palmitoylation

DOI:  https://doi.org/10.1016/j.xcrm.2025.102208
Crit Rev Oncol Hematol. 2025 Jul 02. pii: S1040-8428(25)00213-6. [Epub ahead of print] 104825

Targeting O-GlcNAcylation in Tumor-Associated Inflammation: From Molecular Mechanisms to Cancer Therapy.

Rui Shi, Ling Gao, Shao-Ming Li, Wen-Hao Ren, Ke-Qian Zhi.

  O-GlcNAcylation is a reversible protein post-translational modification. Imbalance in the O-GlcNAcylation cycle plays a crucial role in the occurrence and development of cancer, the therapeutic potential of targeting O-GlcNAcylation in tumor remains underexplored. The inflammatory response is also closely related to the occurrence and development of tumors. Targeting inflammation-related pathways or combining them with other therapies has emerged as a pivotal strategy in cancer intervention. Future research must delve into the spatiotemporal dynamics of tumor-specific inflammatory networks to advance the development of precision therapeutic strategies, a pressing challenge that remains to be addressed in clinical practice.Therefore, exploring the mechanism of action between O-GlcNAcylation and inflammatory response is extremely important for developing new targeted therapies for cancer. The role of inflammation progression regulated by O-GlcNAcylation in the treatment of tumors is summarized, providing a theoretical basis for the development of new targeted therapies in clinical practice.

Keywords:  O-GlcNAcylation; OSCC; inflammation; therapy

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104825