bims-prolim 2025-07-13 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–07–13
eight papers selected by
Bruna Martins Garcia, CABIMER

Post-translational modifications of cancer immune checkpoints: mechanisms and therapeutic strategies.
Research trends of protein palmitoylation in cancer from 2004 to 2024: a bibliometric and visualization analysis.
Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell.
Dysfunctional Decidual CD4+T Cells Induce Recurrent Pregnancy Loss via Palmitoylation-Dependent Tim-3 Lysosomal Sorting and Degradation.
The rise of AMPylation: from bacterial beginnings to modern implications in health and disease.
Histone lactylation-driven YTHDF2 promotes non-small cell lung cancer cell glycolysis and stemness by recognizing m6A modification of SFRP2.
Integrated analysis of single-cell RNA-seq and spatial transcriptomics to identify the lactylation-related protein TUBB2A as a potential biomarker for glioblastoma in cancer cells by machine learning.
Lactate production by tumor-resident Staphylococcus promotes metastatic colonization in lung adenocarcinoma.

Mol Cancer. 2025 Jul 08. 24(1): 193

Post-translational modifications of cancer immune checkpoints: mechanisms and therapeutic strategies.

Haiqing Jia, Lei Jiang, Xiaoyu Shen, Huinan Ye, Xinguang Li, Liwei Zhang, Yanyan Hu, Dandan Song, Hui Jia, Zhe Wang.

  Immunotherapies, particularly immune checkpoint inhibitors (ICIs), have revolutionized cancer clinical management, but low response rates and treatment resistance remain challenging. Protein post-translational modifications (PTMs) are critical for governing protein expression, localization, functions, and interactions with other cellular molecules, which notably build up the diversity and complexity of the proteome. A growing body of evidence supports that PTMs influence immunotherapy efficacy and outcomes by post-translationally modulating the expression and functions of immune checkpoints. Therefore, understanding the PTM mechanisms that govern immune checkpoints is paramount for developing novel treatment strategies to improve immunotherapy efficacy and overcome resistance. This review provides an overview of the current comprehension of the regulatory mechanisms by which PTMs (glycosylation, phosphorylation, ubiquitination, acetylation, succinylation, palmitoylation, lactylation, O-GlcNAcylation, UFMylation, and neddylation) modulate immune checkpoints to unveil potential therapeutic targets. Moreover, this review discusses the potential of therapeutic strategies targeting PTMs of immune checkpoints, providing insights into the combination treatment with ICIs in maximizing the benefits of immunotherapy and overcoming resistance.

Keywords:  Combination treatment; Immune checkpoints; Immunotherapy; Post-translational modifications; Treatment resistance

DOI:  https://doi.org/10.1186/s12943-025-02397-5
Front Oncol. 2025 ;15 1571870

Research trends of protein palmitoylation in cancer from 2004 to 2024: a bibliometric and visualization analysis.

Yufeng Peng, Kewei Peng, Yi Wang, Luyao Li, Yuefei Lu.

   Background: Protein palmitoylation is a dynamic and reversible lipid modification that has attracted increasing attention in cancer research in recent years. Palmitoylation involves the covalent attachment of palmitic acid (C16) to cysteine residues, altering the protein's hydrophobicity and thereby affecting its membrane localization, stability, and functional activity. Recently, palmitoylation has been closely associated with the development and progression of various cancers, making it a key factor in cancer biology research.
Methods: This study conducted a systematic bibliometric analysis using the Web of Science Core Collection (WoSCC) as the data source. A total of 685 papers published between January 1, 2004, and December 31, 2024, on the relationship between protein palmitoylation and cancer were selected. Information such as article titles, abstracts, and keywords was extracted to analyze publication trends, research hotspots, and collaboration networks among authors and institutions, thus assessing the dynamics of research in this field.
Results: The analysis revealed that from 2004 to 2024, a total of 685 papers were published on the relationship between protein palmitoylation and cancer, with a significant increase in publications after 2020. The United States and China are the leading countries in this field, with institutions like Harvard University and the Chinese Academy of Sciences making substantial contributions. Research hotspots have shifted from early mechanistic studies to cancer-specific applications, particularly in areas such as tumor immune evasion, metabolic reprogramming, and therapeutic strategies, where significant progress has been made.
Conclusion: Future efforts should concentrate on three primary directions: constructing high-resolution pan-cancer palmitoylation site maps to unveil subtype-specific modification patterns; developing subtype-selective inhibitors targeting the ZDHHC enzyme family to overcome the toxicity limitations of current broad-spectrum inhibitors; and establishing international research alliances to integrate China's high productivity with the United States' translational expertise, thereby bridging regional disparities between basic research and clinical innovation, ultimately advancing palmitoylation regulatory networks toward precision therapeutic strategies.

Keywords:  bibliometrics; cancer; palmitoylation; research frontiers; visualization analysis

DOI:  https://doi.org/10.3389/fonc.2025.1571870
Sci Rep. 2025 Jul 09. 15(1): 24651

Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell.

Jiang He, Tangmin Lai, Zhiying Zhou, Haonan Yang, Zheng Lei, Liu Zhou, Nan Li, Yu He, Siwei Zeng, Erha Munai, Yuanyuan Tan, Miaomiao Wang, Yang Zhang, Wei Zhou, Yongzhong Wu.

The novel protein acylation modifications have played a vital role in protein post-translational modifications. However, the functions and effects of the protein acylation modifications in lung adenocarcinoma are still uncertain. Currently, there is still a lack of global identification of acylation modifications in lung adenocarcinoma cells. Therefore, in this study, we detected 10 currently known acylation modifications in lung adenocarcinoma cells by Western blot. We found that the abundance of lysine lactylation (Kla), crotonylation (Kcr) and succinylation (Ksu) is likely higher. Subsequently, we identified the above three modifications together with phosphorylation by global mass spectrometry-based proteomics in lung adenocarcinoma cells. As a result, we got 3110 Kla sites in 1220 lactylated proteins, 16,653 Kcr sites in 4137 crotonylated proteins, 4475 Ksu sites in 1221 succinylated proteins, and 15,254 phosphorylation sites in 4139 phosphorylated proteins. Recent studies have highlighted the role of lactylation modifications in tumor cell resistance to radiation and chemotherapy by affecting homologous recombination. Our subsequent investigations have shown that key factors in the nonhomologous end joining (NHEJ) pathway, such as Ku70 and Ku80, undergo lactylation modifications. Inhibition of lactylation impairs the efficiency of nonhomologous end joining. In conclusion, our results provide a proteome-wide database to study Kla, Kcr and Ksu and phosphorylation in lung adenocarcinoma, and new insights into the role of acylation modification in lung adenocarcinoma.

DOI: https://doi.org/10.1038/s41598-025-09937-5
Adv Sci (Weinh). 2025 Jul 11. e00971

Dysfunctional Decidual CD4+T Cells Induce Recurrent Pregnancy Loss via Palmitoylation-Dependent Tim-3 Lysosomal Sorting and Degradation.

Liyuan Cui, Xinhang Meng, Yujie Luo, Jinfeng Qian, Fengrun Sun, Mingke Qiu, Songcun Wang.

  Palmitoylation is a fully reversible post-translational modification that regulates the functions of various proteins. While its dysregulation has been implicated in numerous pathological processes, there has been scarce researches on palmitoylation changes in proteins associated with recurrent pregnancy loss (RPL). Utilizing palmitoylation proteomics, 3262 proteins are identified with increased palmitoylation and 1577 proteins with decreased palmitoylation in the decidual immune cells from RPL patients compared to those from normal early pregnancies. Reduced palmitoylation by 2-bromopalmitate promoted decidual CD4+T (dCD4+T) cell tolerance and decrease the resorption rate of abortion-prone mice, suggesting that elevated palmitoylation level may be associated with RPL. The bioinformatics, proteomic, functional and mouse model studies revealed that T cell immunoglobulin domain and mucin domain-3 (Tim-3) is palmitoylated by ZDHHC3 on cysteine 9 residue. This palmitoylated-Tim-3 subsequently bound to sortilin and was directed to lysosome for degradation, leading to decreased expression of Tim-3 and the dysfunction of dCD4+T cells, ultimately resulting in fetal loss. We elucidated a pivotal role for dynamic palmitoylation in RPL and uncovered a novel mechanism governing Tim-3 regulation. Given that Tim-3 dysregulation is frequently linked to RPL, our findings may have important implications for understanding the etiology of RPL and developing targeted therapy of RPL.

Keywords:  Tim‐3; decidual CD4+T cells; maternal‐fetal tolerance; palmitoylation; recurrent pregnancy loss

DOI:  https://doi.org/10.1002/advs.202500971
Biochem Soc Trans. 2025 Jul 08. pii: BST20253056. [Epub ahead of print]

The rise of AMPylation: from bacterial beginnings to modern implications in health and disease.

Meghomukta Mukherjee, Anju Sreelatha.

  Protein AMPylation is a post-translational modification in which adenosine monophosphate (AMP) from ATP is covalently attached to a target protein via a phosphodiester bond. This reaction is catalyzed by AMPylases, a diverse group of enzymes containing adenylyltransferase, filamentation induced by cyclic AMP (FIC), or kinase domains. As a reversible modification, AMPylation is dynamically regulated by both writer enzymes (AMPylases) and eraser enzymes (deAMPylases). Since its initial discovery in bacterial nitrogen metabolism in 1967, AMPylation has been recognized as a critical regulatory mechanism in both prokaryotic and eukaryotic systems. Recent studies link AMPylation to neurological disorders, diabetes, and cancer metastasis, underscoring its physiological and pathological significance. In this review, we present an overview of the discovery of AMPylases and deAMPylases, highlighting their role in cellular signaling, stress response, and host-pathogen interactions.

Keywords:  AMP transferase; FIC domain; adenylylation; post-translational modification; unfolded protein response

DOI:  https://doi.org/10.1042/BST20253056
Biochem Pharmacol. 2025 Jul 04. pii: S0006-2952(25)00362-4. [Epub ahead of print]240 117097

Histone lactylation-driven YTHDF2 promotes non-small cell lung cancer cell glycolysis and stemness by recognizing m6A modification of SFRP2.

Shu Zhao, Jing Cheng, Gang Zhou, Longyun Tao, Jiaojiao Xing, Lulu Liu, Zhenhong Chen, Peng Song.

  Histone lactylation is involved in non-small cell lung cancer (NSCLC) by transcriptional regulation of gene expression. YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) is a N6-methyladenosine (m6A) "reader" that recognizes m6A methylation of mRNA and can be regulated by histone lactylation. This study aimed to investigate the role of histone lactylation in NSCLC and the underlying mechanism using in vitro experiments. Glycolysis and stemness were evaluated to assess cellular phenotypes. The effect of histone lactylation on YTHDF2 was evaluated by chromatin immunoprecipitation. The regulation of YTHDF2 on the downstream factor was assessed using RNA immunoprecipitation and dual-luciferase reporter analysis. The results showed that histone H3 lysine 18 lactylation (H3K18la) levels were increased in NSCLC tissues and cells. 2-deoxyglucose (2-DG) or sodium oxamate inhibited H3K18la, while Nala promoted H3K18la. Knockdown of lactate dehydrogenase A/B (LDHA and LDHB) suppressed glycolysis and cancer stemness in NSCLC cells. H3K18la was enriched in the promoter of YTHDF2, which was highly expressed in NSCLC. Knockdown of YTHDF2 suppressed NSCLC cell glycolysis and stemness, while its overexpression promoted the cellular behaviors. Moreover, YTHDF2 interacted with and recognized the m6A methylated secreted frizzled-related protein 2 (SFRP2), and knockdown of SFRP2 counteracted the inhibition of glycolysis and stemness. The animal experiments showed that YTHDF2 knockdown inhibited tumor growth and stemness by upregulating SFRP2 expression. In conclusion, histone lactylation transcriptionally activates YTHDF2 acts as an oncogene in NSCLC by promoting glycolysis and tumor stemness by recognizing m6A methylation of SFRP2. The findings suggest a novel epigenetic regulatory pathogenesis in NSCLC.

Keywords:  Glycolysis; H3K18 lactylation; Non-small cell lung cancer; SFRP2; YTHDF2

DOI:  https://doi.org/10.1016/j.bcp.2025.117097
Front Immunol. 2025 ;16 1601533

Integrated analysis of single-cell RNA-seq and spatial transcriptomics to identify the lactylation-related protein TUBB2A as a potential biomarker for glioblastoma in cancer cells by machine learning.

Yifan Xu, Chonghui Zhang, Jinpeng Wu, Pin Guo, Nan Jiang, Chao Wang, Yugong Feng.

   Background: An increasing number of studies have revealed a link between lactylation and tumor initiation and progression. However, the specific impact of lactylation on inter-patient heterogeneity and recurrence in glioblastoma (GBM) remains to be further elucidated.
Methods: We employed functional enrichment algorithms, including AUCell and UCell, to assess lactylation activity in GBM cancer cells. Additionally, we introduced the interquartile range (IQR) method based on a set of lactylation-related genes (LRGs) to reevaluate the extent of lactylation production within the cancer population at the single-cell resolution. By reconstructing the spatial transcriptomics of hematoxylin and eosin (HE)-stained sections, we further evaluated the lactylation activity in GBM tissues. Subsequently, We employed machine learning algorithms to identify hub genes significantly associated with elevated lactylation levels in GBM. Finally, we experimentally validated the emulsification efficiency and quantified the expression levels of hub genes in human GBM samples.
Results: Our study innovatively demonstrated a markedly elevated global lactylation level in GBM and validated it as an independent prognostic factor for GBM. We established a prognostic gene model associated with emulsification in GBM. Furthermore, the machine learning-based model identified SSBP1, RPA3 and TUBB2A as potential biomarkers for GBM. Notably, the expression levels of these three hub genes and the lactylation level of TUBB2A in GBM tissues were significantly higher compared to those in normal tissues.
Conclusions: We propose and validate a IQR lactylation screening method that provides potential insights for GBM therapy and an effective framework for developing gene screening models applicable to other diseases and pathogenic mechanisms.

Keywords:  IQR; glioblastoma; lactylation; single-cell RNA sequencing; spatial transcriptomics

DOI:  https://doi.org/10.3389/fimmu.2025.1601533
Cell Host Microbe. 2025 Jul 09. pii: S1931-3128(25)00242-2. [Epub ahead of print]33(7): 1089-1105.e7

Lactate production by tumor-resident Staphylococcus promotes metastatic colonization in lung adenocarcinoma.

Huan Yu, Yang Du, Yuling He, Yifan Sun, Junfeng Li, Bo Jia, Jiale Chen, Xinya Peng, Tongtong An, Jianjie Li, Yujia Chi, Man Wang, Lihua Cao, Yidi Tai, Xiaoyu Zhai, Reyizha Nuersulitan, Sheng Li, Nan Wu, Jia Wang, Hongchao Xiong, Shujie Wan, Jiaming Liu, Xuelian Yang, Xingsheng Hu, Dongmei Lin, Wei Sun, Yue Wang, Guo An, Xumeng Ji, Lingdong Kong, Lu Ding, Yunan Ma, Zhihua Tian, Bin Dong, Yujing Bi, Jianmin Wu, Ziping Wang.

  The role of the lung microbiota in cancer remains unclear. Here, we reveal that Staphylococcus is selectively enriched in metastatic tumor lesions and is associated with tumor recurrence in lung cancer patients. Using patient-derived bacterial strains, we employ a combination of cell line, organoid, mouse allograft, and xenograft models to demonstrate that S. nepalensis and S. capitis promote the metastatic potential of lung cancer cells. Mechanistically, lactate secreted by S. nepalensis and S. capitis upregulates MCT1 expression in tumor cells, facilitating lactate uptake and activating pseudohypoxia signaling. These effects can be eliminated by knocking out the lactate-producing genes (D-lactate dehydrogenase [ddh]/L-lactate dehydrogenase [ldh]) in the bacterial strains. Furthermore, we show that inhibiting MCT1 attenuates Staphylococcus-induced tumor metastasis both in vitro and in vivo. Collectively, our results demonstrate that tumor-resident Staphylococcus species promote lung cancer metastasis by activating host pseudohypoxia signaling and further identify key regulators as potential targets for therapeutic development.

Keywords:  MCT1; NDRG1; Staphylococcus capitis; Staphylococcus nepalensis; lactate; lung adenocarcinoma metastasis

DOI:  https://doi.org/10.1016/j.chom.2025.06.013