bims-prolim 2025-07-27 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–07–27
six papers selected by
Bruna Martins Garcia, CABIMER

Potential therapeutic target in oncology: Protein palmitoylation (Review).
Identification of lactylation-associated immune and metabolic regulators in bladder cancer via integrated bulk and single-cell transcriptomics.
The Role of Lactate in Cancer Immunotherapy: Mechanisms and Applications.
Cancer associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer.
KRAS mutation increases histone H3 lysine 9 lactylation (H3K9la) to promote colorectal cancer progression by facilitating cholesterol transporter GRAMD1A expression.
Short-chain acyl post-translational modifications in cancers: Mechanisms, roles, and therapeutic implications.

Oncol Rep. 2025 Oct;pii: 117. [Epub ahead of print]54(4):

Potential therapeutic target in oncology: Protein palmitoylation (Review).

Shiping Hao, Yongming Mei, Shaolin Chen, Jing Liu, Yao Zhang, Zhengfeng Zhu, Kangjia Zuo.

  Post‑translational modifications (PTMs) of proteins, by altering the structural conformation of precursor polypeptides, play an indispensable role in augmenting the diversity and stability of the proteome. PTMs exert profound influence on various hallmarks of tumor biology, including cellular proliferation, apoptosis, angiogenesis and metastatic dissemination. Accordingly, advancing our understanding of PTMs holds substantial promise for broadening the therapeutic landscape of oncology. Among these modifications, palmitoylation, a reversible lipid‑based PTM, critically modulates protein stability, membrane localization, protein‑protein interactions and signal transduction cascades. Dysregulation of palmitoylation has been increasingly implicated in tumorigenesis, suggesting its aberrant forms as putative targets for therapeutic intervention. The present review delineates the biochemical mechanisms underlying protein palmitoylation and synthesizes current insights into its multifaceted roles in tumor progression, immune modulation and metabolic regulation, thereby offering novel perspectives for the development of targeted cancer therapies.

Keywords:  cancer; palmitoylation; post‑translational modification; therapeutic target

DOI:  https://doi.org/10.3892/or.2025.8950
Front Immunol. 2025 ;16 1604758

Identification of lactylation-associated immune and metabolic regulators in bladder cancer via integrated bulk and single-cell transcriptomics.

Yanjun Chen, Yu Sun, Xiaoyan Liu.

   Background: Lactate-driven metabolic reprogramming and histone lactylation play pivotal roles in bladder cancer (BLCA) progression, yet their underlying mechanisms and regulatory genes remain poorly understood.
Methods: Using transcriptomic data from The Cancer Genome Atlas (TCGA), we identified lactylation-associated genes and constructed a prognostic signature. Comprehensive bioinformatics analyses were conducted to assess immune infiltration, tumor microenvironment characteristics, and the lactylation landscape at the single-cell level. Furthermore, we performed in vitro experiments to evaluate the biological functions of key lactylation-related genes in BLCA cells.
Results: Six lactylation-related hub genes were identified, among which FASN and RUNX2 were significantly upregulated in BLCA and associated with poor prognosis. Single-cell analyses revealed elevated lactylation signatures in tumor epithelial and immune cells. Knockdown of FASN or RUNX2 in BLCA cell lines significantly suppressed cell proliferation, induced apoptosis, and reduced intracellular lactate levels. Correspondingly, global protein lactylation was diminished, with dominant modification signals observed around 40 kDa, indicating a potential set of non-histone proteins as key functional targets.
Conclusions: Our study highlights a metabolic-enzymatic axis wherein FASN and RUNX2 regulate lactate-driven protein lactylation in BLCA. These findings provide new insights into the non-histone functions of lactylation and suggest potential therapeutic targets at the intersection of metabolism and tumor immunity.

Keywords:  bladder cancer; immunological regulators; lactylation; metabolic regulators; single cell

DOI:  https://doi.org/10.3389/fimmu.2025.1604758
Curr Cancer Drug Targets. 2025 Jul 17.

The Role of Lactate in Cancer Immunotherapy: Mechanisms and Applications.

Yunhui Fan, Haoyue Jia, Wanguang Zhang.

  In recent years, immunotherapy has demonstrated significant clinical effectiveness. However, challenges such as low response rates, severe treatment-related side effects, and acquired immune tolerance persist in tumor immunotherapy. Metabolic dysregulation is acknowledged as a principal factor in tumor growth, with aerobic glycolysis, or the Warburg effect, being a defining characteristic of numerous cancers. The enhanced uptake of glucose and glycolysis provides the necessary intermediates for anabolic reactions, which are essential for the proliferation of cancer cells, while simultaneously supplying sufficient energy. How-ever, the concomitant increase in lactate production contributes to immunosuppression within the tumor microenvironment. Tumor cells exploit lactate anabolism, lactate shuttling, and ly-sine lactylation modifications, which significantly diminish the efficacy of immunotherapy. The treatment targeting lactate anabolism or lactate transport proteins may prove an effective strategy for enhancing the effectiveness of cancer immunotherapy. This review provides a comprehensive overview of the role of lactate in anti-tumor immunotherapy, with the objective of deepening the understanding of the importance of lactate monitoring in cancer treatment. By elucidating these mechanisms, we aim to suggest innovative avenues for clinical cancer management, potentially improving therapeutic outcomes and overcoming the existing limita-tions of immunotherapy.

Keywords:  Lactate; cancer; immune; immunotherapy; lactic acid.; tumor

DOI:  https://doi.org/10.2174/0115680096373625250701095509
Cancer Lett. 2025 Jul 17. pii: S0304-3835(25)00485-9. [Epub ahead of print]631 217917

Cancer associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer.

Jiahua He, Weihao Li, Song Wang, Jin Lan, Xuanlin Hong, Leen Liao, Da Kang, Weifeng Wang, Ruowei Wang, Weili Zhang, Long Yu, Qingjian Ou, Yujing Fang, Xiaojun Wu, Junzhong Lin, Peirong Ding, Chi Zhou, Zhizhong Pan, Jianhong Peng.

  Oxaliplatin is widely used in chemotherapy for patients with advanced colorectal cancer (CRC). However, frequent drug resistance limits its therapeutic efficacy in patients. Here, we found that a subset of cancer associated fibroblasts (CAFs) with activated glycolysis induced CRC resistance to oxaliplatin. Lactate derived from CAFs promoted the transcription of ANTXR1 through histone lactylation and induced ANTXR1 lactylation at lysine 453 residue. The increased expression of ANTXR1 and ANTXR1 K453la in CRC cells was correlated with oxaliplatin resistance in CRC cells and the poor prognosis of CRC patients. Mechanistically, lactylation promoted ANTXR1 stability and activated the RhoC/ROCK1/SMAD5 signal pathway, subsequently contributed to CRC stemness and oxaliplatin resistance. Genetic or pharmacologic inhibition of the lactate shuttle between CAFs and cancer cells improved chemotherapy efficiency in vitro and in cell/patient-derived xenograft models. These findings contribute to a better understanding of oxaliplatin resistance and indicates that inhibition of tumor-stromal interactions might be an attractive strategy for enhancing the efficacy of oxaliplatin.

Keywords:  ANTXR1; Cancer associated fibroblasts; Colorectal cancer; Lactylation; Oxaliplatin

DOI:  https://doi.org/10.1016/j.canlet.2025.217917
Cell Death Differ. 2025 Jul 24.

KRAS mutation increases histone H3 lysine 9 lactylation (H3K9la) to promote colorectal cancer progression by facilitating cholesterol transporter GRAMD1A expression.

Chi Zhang, Runfeng Yu, Senmao Li, Ming Yuan, Tuo Hu, Jiaqi Liu, Haoxian Ke, Shubiao Ye, Jihye Yun, Junfeng Huang, Guanzhan Liang, Shaopeng Chen, Xianrui Wu, Ping Lan.

Histone lactylation is a novel epigenetic modification derived from lactate, but its role and mechanism in KRAS mutant colorectal cancer (CRC) progression remains to be fully elucidated. In this study, we first showed that mutant KRAS increased H3 lysine 9 lactylation (H3K9la) to promote CRC progression. We found that KRAS-mutant CRC tissues and cell lines exhibited higher lactylation and H3K9la levels compared to KRAS wild-type counterparts, driven by increased intracellular lactate. Elevated lactylation and H3K9la levels were associated with poor prognosis and advanced clinical stages. Inhibition of lactylation and H3K9la suppressed proliferation and migration of CRC cells. Mechanistically, mutant KRAS upregulated GRAMD1A expression by elevating H3K9la levels to increase chromatin accessibility. And increased GRAMD1A facilitated cholesterol metabolism to promote CRC growth and metastasis. Targeted inhibition of H3K9la or GRAMD1A reduced tumor growth in CRC patient-derived xenografts (PDX) models. Our study uncovered the critical role of H3K9la as a novel epigenetic modification in KRAS mutant CRC progression, suggesting H3K9la and its downstream gene GRAMD1A as promising targets for therapeutic intervention in KRAS mutant CRC and potential biomarkers for the prognosis of CRC patients.

DOI: https://doi.org/10.1038/s41418-025-01533-4
Cancer Commun (Lond). 2025 Jul 24.

Short-chain acyl post-translational modifications in cancers: Mechanisms, roles, and therapeutic implications.

Ting Wu, Yingqi Zhao, Xin Zhang, Yuanhe Wang, Qiuchen Chen, Mingrong Zhang, Huan Sheng, Yuying Zhang, Jinyu Guo, Jun Li, Yuxuan Fan, Ziqing Wang, Yalun Li, Haoran Wang, Minjie Wei, Xiaoyun Hu, Huizhe Wu.

  Post-translational modifications (PTMs) play a pivotal role in epigenetic regulation and are key pathways for modulating protein functionality. PTMs involve the covalent attachment of distinct chemical groups, such as succinyl, crotonyl, and lactyl, at specific protein sites, which alter protein structure, function, stability, and activity, ultimately influencing biological processes. Recently, metabolically derived short-chain acylation modifications (with acyl groups containing fewer than six carbon atoms) have been progressively identified, such as butyrylation, succinylation, crotonylation, and lactylation, differing from traditional acetylation in structure, physicochemical properties, function, and regulation. Aberrant short-chain acyl-PTMs are often associated with tumorigenesis. Research highlights that PTMs like succinylation and lactylation are essential in regulating tumor metabolism, drug resistance, and immune responses. This review elucidates the regulatory mechanisms of eight short-chain acyl-PTMs-butyrylation, succinylation, crotonylation, malonylation, glutarylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, and lactylation-that are involved in tumor initiation and progression. Their roles in controlling tumor genomic stability, gene transcription, protein stability, enzyme activity, and nuclear localization are summarized, demonstrating their impact on related biological processes such as tumor metabolism, multi-drug resistance, and immune evasion. Additionally, the review provides an overview of current drug research targeting enzymes that regulate PTMs, offering critical insights to advance therapeutic strategies for cancer treatment.

Keywords:  cancer; drug resistance; enzyme activity; gene transcription; genomic stability; metabolism; nuclear localization; protein stability; short‐chain acyl post‐translational modifications

DOI:  https://doi.org/10.1002/cac2.70048