bims-prolim 2025-08-24 papers

Issue of 2025–08–24
four papers selected by
Bruna Martins Garcia, CABIMER

Cancer Commun (Lond). 2025 Aug 19.

Lactylation in cancer biology: Unlocking new avenues for research and therapy.

Xiaoyu Hou, Zhenya Hong, Huimin Zen, Changyi Zhang, Peng Zhang, Ding Ma, Zhiqiang Han.

Lactylation, a newly identified post-translational modification, plays a multifaceted role in cancer biology by integrating epigenetic and non-epigenetic mechanisms. This review summarizes the latest research progress on lactylation, including its functions in epigenetic regulation and its broader impact on cellular processes. Lactate, as a metabolic byproduct, not only serves as an energy source for tumor cells but also acts as a signaling molecule driving various oncogenic processes. Lactylation facilitates cancer metabolic reprogramming, enabling tumor cells to adapt to hypoxic and nutrient-deprived microenvironments. Moreover, lactylation mediates immune suppression in the tumor microenvironment, promoting immune evasion and therapy resistance. This review further explores the clinical potential of targeting lactylation, offering new avenues for innovation in cancer research and treatment. These findings highlight the pivotal role of lactylation in cancer progression and its significant value as a potential therapeutic target.

Keywords: Lactylation; Metabolic reprogramming; Post‐translational modification; Tumor microenvironment

DOI: https://doi.org/10.1002/cac2.70054

Front Pharmacol. 2025 ;16 1634985

Integrative analysis of lactylation related genes in prostate cancer: unveiling heterogeneity through single-cell RNA-seq, bulk RNA-seq and machine learning.

Chenghao Zhou, Lifeng Ding, Huailan Wang, Gonghui Li, Lei Gao.

Introduction: Lactylation, a post-translational modification characterized by the attachment of lactate to protein lysine residues on proteins, plays a pivotal role in cancer progression and immune evasion. However, its implications in immunity regulation and prostate cancer prognosis remains poorly understood. This study aims to systematically examine the impact of lactylation-related genes (LRGs) on prostate cancer.
Methods: Single-cell and bulk RNA sequencing data from patients with prostate cancer were analyzed. Data were sourced from TCGA-PRAD, GSE116918, and GSE54460, with batch effects mitigated using the ComBat method. LRGs were identified from exisiting literature, and unsupervised clustering was applied to assess their prognostic siginificance. The tumor microenvironment and functional enrichment of relevant pathways were also evaluated. A prognostic model was developed using integrative machine learning techniques, with drug sensitivy analysis included. The mRNA expression profiles of the top ten genes were validated in clinical samples.
Results: Single-cell RNA sequencing revealed distinct lactylation signatures across various cell types. Bulk RNA-seq analysis identified 56 prognostic LRGs, classifying patients into two distinct clusters with divergent prognoses. The high-risk cluster exhibited reduced immune cell infiltration and increased resistance to specific targeted therapies. A machine learning-based prognostic signature was developed, demonstrating robust predictive accuracy for treatment responses and disease outcomes.
Conclusion: This study offers a comprehensive analysis of lactylation in prostate cancer, identifying potential prognostic biomarkers. The proposed prognostic signature provides a novel approach to personalized treatment strategies, deepening our understanding of the molecular mechanisms driving prostate cancer and offering a tool for predicting therapeutic responses and clinical outcomes.

Keywords: immune microenvironment; lactylation; machine learning; personalized treatment; prognostic biomarker; prostate cancer

DOI: https://doi.org/10.3389/fphar.2025.1634985

Biochem Biophys Res Commun. 2025 Aug 13. pii: S0006-291X(25)01203-3. [Epub ahead of print]780 152488

CPT1A promotes the proliferation and immune evasion of lung cancer by inducing CTLA-4 K154 succinylation.

Wencui Kong, Jingrong Yang, Xingfeng Qi, Zongyang Yu, Guo Li, Zhongquan Zhao.

As a succinylation transferase, CPT1A can promote the progression of various tumors relying on succinylation modification, but its mechanism in lung cancer (LC) progression and immune evasion remains unclear. Detect mRNA expression using RT-qPCR. Protein expression, protein stability, and succinylation levels were detected by Western blot analysis. Cell transfection technology is used for knockdown and overexpression of genes. Use relevant kits to detect cytotoxicity and secretion levels of inflammatory factors. To detect cell proliferation activity, CCK-8 and clonogenic assays were used. Identification of protein interactions using coimmunoprecipitation. Antitumor effects were evaluated using xenograft tumor models. The succinyltransferase CPT1A was highly elevated in LC, and its knockdown inhibited the proliferation of LC cells and upregulated the levels of toxic and inflammatory factor secretion induced by CD8+ T cells. However, these effects can be partially reversed by overexpression of CTLA-4. Furthermore, CPT1A knockdown inhibited tumor growth in LC xenograft tumor models and promoted tumor cell apoptosis. Western blot and co-immunoprecipitation results revealed that CPT1A caused succinylation of CTLA-4 K154 site, thereby enhancing protein stability. CPT1A induces CTLA-4 succinylation at the K154 site, enhances its protein stability, promotes the proliferation of LC cells in vivo and in vitro, and inhibits the toxicity and inflammatory responses induced by CD8+ T cells.

Keywords: CPT1A; CTLA-4; Immune evasion; Lung cancer; Tumor progression

DOI: https://doi.org/10.1016/j.bbrc.2025.152488

Eur J Immunol. 2025 Aug;55(8): e70039

TLR9-Driven S-Palmitoylation in Dendritic Cells Reveals Immune and Metabolic Protein Targets.

Juan N Quiroz, Malte Sielaff, Daria Kondrateva, Fatima Boukhallouk, Gloria J Godoy, Cecilia R Molina, Brecht Moonen, Claudia C Motran, Jeroen Bogie, Hugo D Luján, Stefan Tenzer, Tim Sparwasser, Luciana Berod.

Dendritic cells (DCs) rely on Toll-like receptor 9 (TLR9) to detect unmethylated CpG motifs in microbial DNA, triggering essential immune responses. While the downstream signaling pathways of TLR9 activation are well characterized, their impact on S-palmitoylation is unknown. S-palmitoylation, involving the reversible attachment of palmitic acid to cysteine residues, plays a crucial role in regulating protein function and is catalyzed by the ZDHHC family of palmitoyl-acyltransferases (PATs). In this study, we investigated the S-palmitoylated proteome of bone marrow-derived GM-CSF DCs (GM-DCs) at resting and following TLR9 activation with CpGB. Using the click-chemistry-compatible analog 17-octadecynoic acid (17-ODYA) and mass spectrometry (MS)-based proteomics, we characterized dynamic remodeling of S-palmitoylation in response to TLR9 activation. This included enrichment of targets involved in immune and metabolic pathways. Transcriptomic analysis of mice and human DCs revealed TLR9-driven modulation of PAT-encoding genes. Subsequently, we explored the contribution of Zdhhc9 expression to the regulation of S-palmitoylation in DCs. Using gene knockout approaches, we identified candidate protein targets potentially linked to ZDHHC9 activity. Interestingly, modulation of Zdhhc9 expression alone did not influence DC maturation, suggesting that other PATs might compensate for its activity. Together, our findings reveal a novel layer of regulation in TLR9 signaling mediated by S-palmitoylation.

Keywords: S‐palmitoylation; TLR9 signaling; dendritic cells; innate immunity

DOI: https://doi.org/10.1002/eji.70039