bims-prolim 2025-06-29 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–06–29
seven papers selected by
Bruna Martins Garcia, CABIMER

Lactate-Mediated Crosstalk Between Tumor Cells and Cancer-Associated Fibroblasts: Mechanisms and Therapeutic Opportunities.
Targeting S-Nitrosylation to Overcome Therapeutic Resistance in NRAS-Driven Melanoma.
Palmitoylation regulators drive the progression of clear cell renal cell carcinoma through Inhibition of cuproptosis: insights into the role of ZDHHC18.
Sirtuin 5 inhibits mitochondrial metabolism in liver cancer cells and promotes apoptosis by mediating the desuccinylation of CS.
MTPrompt-PTM: A Multi-Task Method for Post-Translational Modification Prediction Using Prompt Tuning on a Structure-Aware Protein Language Model.
Riplet promotes lipid metabolism changes associated with CD8 T cell exhaustion and anti-PD-1 resistance in hepatocellular carcinoma.
The significance of protein N-glycosylation in the pathogenesis of lung cancer and its clinical implications.

Int J Mol Sci. 2025 Jun 11. pii: 5583. [Epub ahead of print]26(12):

Lactate-Mediated Crosstalk Between Tumor Cells and Cancer-Associated Fibroblasts: Mechanisms and Therapeutic Opportunities.

Siqi Tan, Faxiao Zhou, Xiaoming Wu.

  Lactate is a key oncometabolite that plays a critical role in modulating the behavior and function of both tumor cells and tumor-associated stromal cells within the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), as essential stromal components, engage in dynamic crosstalk with tumor cells through lactate-mediated signaling pathways. Elevated lactate levels in the TME primarily originate from metabolic reprogramming in tumor cells and CAFs. Notably, tumor-derived lactate not only promotes basement membrane remodeling and epithelial-mesenchymal transition (EMT) in CAFs but also influences their functional phenotype. Conversely, CAF-secreted lactate significantly contributes to tumor progression. Therapeutic strategies targeting lactate transport and metabolism-particularly through the inhibition of monocarboxylate transporters (MCTs) and lactate dehydrogenase (LDH)-have emerged as promising approaches in cancer treatment. This review summarizes the multifaceted roles of lactate and lactylation, elucidates the molecular mechanisms underlying lactate-mediated tumor-CAF crosstalk, and explores potential therapeutic interventions targeting lactate metabolism and CAFs.

Keywords:  CAFs; TME; lactate; lactation

DOI:  https://doi.org/10.3390/ijms26125583
Cancers (Basel). 2025 Jun 17. pii: 2020. [Epub ahead of print]17(12):

Targeting S-Nitrosylation to Overcome Therapeutic Resistance in NRAS-Driven Melanoma.

Jyoti Srivastava, Sanjay Premi.

  NRAS-mutant melanoma represents a clinically challenging subset of melanoma with limited effective therapies and intrinsic resistance to targeted MEK inhibition. Recent findings highlight protein S-nitrosylation, a redox-dependent post-translational modification as a critical modulator of MEK-ERK signaling and immune evasion in this context. In this commentary, we discuss how S-nitrosylation of MAPK components, including MEK and ERK, sustains oncogenic signaling and attenuates immunogenic cell death. Targeting this modification with nitric oxide synthase (NOS) inhibitors such as L-NAME, L-NMMA and 1400w restore sensitivity of MEK inhibitor, promotes dendritic cell activation, and enhances CD8+ T cell infiltration in preclinical models such as immunogenic mouse models and individual patient derived, primary melanoma cells. We also explore the emerging role of S-nitrosylation in regulating macrophage-mediated immune surveillance and propose translational strategies for combining redox modulation with targeted and immune therapies. These insights offer a compelling framework for overcoming therapeutic resistance and reprogramming the tumor immune microenvironment to activate the cytotoxic T-cells and enhance the responses to immunotherapy in NRAS-driven cancers.

Keywords:  MEK-ERK signaling; NRAS-mutant melanoma; S-Nitrosylation; drug resistance; immune evasion; immunogenic cell death; redox modulation; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17122020
Cancer Cell Int. 2025 Jun 23. 25(1): 230

Palmitoylation regulators drive the progression of clear cell renal cell carcinoma through Inhibition of cuproptosis: insights into the role of ZDHHC18.

Wei Xu, Xiao-Chao Chen, Yang Wang, Jian-Chun Chen, Zhi-Jun Cao, Ru Huang, Chao Chen, Dao-Rong Hou, Min-Jun Jiang, Chen Xu.

   BACKGROUND: Protein palmitoylation is a reversible post-translational modification that increases protein hydrophobicity, which can affect protein localization, stability, and function. Although palmitoylation is frequently observed in various cancers, the specific mechanisms by which it influences clear cell renal cell carcinoma (ccRCC) are still not well understood.
METHODS: This study used transcriptome expression profiles and clinical characteristics of clear cell renal cell carcinoma (ccRCC) obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Kaplan-Meier (KM) survival analysis was performed to evaluate patient survival. Consensus clustering was applied to identify tumor palmitoylation patterns. A total of 101 different machine learning methods were used to develop predictive models. Functional enrichment analyses were conducted using Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Variation Analysis (GSVA).
RESULTS: Of the 34 prognosis-related palmitoylation-related genes (PRGs), 29 were used to cluster patients in the TCGA-KIRC cohort, leading to the identification of four palmitoylation clusters. We developed a risk model and a nomogram based on palmitoylation scores to enhance risk classification. Functional analysis indicated that high-risk patients exhibited disrupted fatty acid metabolism. Correlation analysis identified ZDHHC18 as a potential hub gene associated with impaired fatty acid metabolism and cuproptosis. Finally, we validated the role of ZDHHC18 in ccRCC proliferation through in vitro experiments.
CONCLUSION: Our research demonstrated that PRGs play a crucial role in the development of clear cell renal cell carcinoma (ccRCC). A nomogram based on palmitoylation scores may accurately predict the prognosis of ccRCC patients. Furthermore, the palmitoylation regulator ZDHHC18 affects cuproptosis in ccRCC, which in turn impacts patient survival.

Keywords:  CcRCC; Cuproptosis; Protein s-palmitoylation; ZDHHC18

DOI:  https://doi.org/10.1186/s12935-025-03882-z
Front Immunol. 2025 ;16 1560989

Sirtuin 5 inhibits mitochondrial metabolism in liver cancer cells and promotes apoptosis by mediating the desuccinylation of CS.

Huimin Cao, Dongsheng Wei, Han Li, Mei Zhao, Yixin Ma, Liang Kong, Guoyuan Sui, Lianqun Jia.

   Background: Citrate synthase (CS) is a key rate-limiting enzyme in the tricarboxylic acid (TCA) cycle and plays a crucial role in cancer progression. However, the mechanism by which CS promotes liver cancer growth remains unclear. The aim of this study is to elucidate the role of CS and its post-translational modifications (PTMs) in the initiation and progression of hepatocellular carcinoma (HCC).
Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect protein lysine succinylation in human liver cancer and adjacent non-cancerous tissues. A HCC model was established in male C57BL/6 mice through intraperitoneal injection of DEN. The expression of SIRT5 and CS in HCC mice was assessed by RT-qPCR, immunohistochemistry, and Western blotting. HepG2 cells were cultured, and co-immunoprecipitation (Co-IP) was performed to evaluate the interaction between SIRT5 and CS. Western blotting was used to measure the succinylation levels of CS. In addition, Mito-Tracker Red CMXRos staining, reactive oxygen species (ROS) measurement, ATP level assay, EdU cell proliferation assay, colony formation assay, TUNEL staining, and flow cytometry were used to investigate the effects of CS succinylation and desuccinylation on mitochondrial function and cell proliferation in hepatocellular carcinoma cells.
Results: A total of 358 differentially modified proteins were identified in human liver cancer tissues. These differentially modified proteins were primarily enriched in the mitochondria, and CS exhibited high levels of succinylation in HCC tissues. In mouse liver cancer tissues, SIRT5 expression was reduced while CS expression was increased. Furthermore, SIRT5 was found to interact with CS, mediating the de-succinylation of CS at the lysine 375 site. Additionally, succinylation at the K375 site of CS was shown to enhance mitochondrial activity and ATP content in HepG2 cells, while reducing intracellular ROS levels and promoting cell proliferation. In contrast, de-succinylation of CS at the K375 site significantly impaired mitochondrial function and ATP levels, increased ROS levels, and induced apoptosis in HepG2 cells.
Conclusion: Succinylation of CS is crucial for maintaining mitochondrial function and promoting cell proliferation in liver cancer cells. Targeting SIRT5-mediated de-succinylation of CS may represent a promising therapeutic strategy for the treatment of hepatocellular carcinoma.

Keywords:  PTMs (post-translational modifications); apoptosis; citrate synthase; hepatocellular carcinoma; mitochondrial metabolism; succinylation

DOI:  https://doi.org/10.3389/fimmu.2025.1560989
Biomolecules. 2025 Jun 09. pii: 843. [Epub ahead of print]15(6):

MTPrompt-PTM: A Multi-Task Method for Post-Translational Modification Prediction Using Prompt Tuning on a Structure-Aware Protein Language Model.

Ye Han, Fei He, Qing Shao, Duolin Wang, Dong Xu.

  Post-translational modifications (PTMs) regulate protein function, stability, and interactions, playing essential roles in cellular signaling, localization, and disease mechanisms. Computational approaches enable scalable PTM site prediction; however, traditional models focus only on local sequence features from fragments around potential modification sites, limiting the scope of their predictions. Recently, pre-trained protein language models (PLMs) have improved PTM prediction by leveraging biological knowledge derived from extensive protein databases. However, most PLMs used for PTM site prediction are pre-trained solely on amino acid sequences, limiting their ability to capture the structural context necessary for accurate PTM site prediction. Moreover, these methods typically train separate single-task models for each PTM type, which hinders the sharing of common features and limits potential knowledge transfer across tasks. To overcome these limitations, we introduce MTPrompt-PTM, a multi-task PTM prediction framework developed by applying prompt tuning to a structure-aware protein language model (S-PLM). Instead of training several single-task models, MTPrompt-PTM trains one multi-task model to predict multiple types of PTM sites using shared feature extraction layers and task-specific classification heads. Additionally, we incorporate a knowledge distillation strategy to enhance the efficiency and generalizability of multi-task training. Experimental results demonstrate that MTPrompt-PTM outperforms state-of-the-art PTM prediction tools on 13 types of PTM sites, highlighting the advantages of multi-task learning and structural integration.

Keywords:  knowledge distillation; multi-task prediction; post-translational modification prediction; prompt tuning; structure-aware protein language model (S-PLM)

DOI:  https://doi.org/10.3390/biom15060843
Sci Immunol. 2025 Jun 27. 10(108): eado3485

Riplet promotes lipid metabolism changes associated with CD8 T cell exhaustion and anti-PD-1 resistance in hepatocellular carcinoma.

Junnan Liang, Jingyu Liao, Ruizhi Chang, Wenlong Jia, Ganxun Li, Zeyu Chen, Hang Wu, Chang Zhu, Jingyuan Wen, Qibo Huang, Han Gao, Zichen Gui, Weiqi Xu, Huifang Liang, Qiumeng Liu, Dafeng Xu, Zifu Li, Limin Xia, Xiaoping Chen, Zhao Huang, Wanguang Zhang, Zeyang Ding, Bixiang Zhang.

The overall response rate to immunotherapy is modest in hepatocellular carcinoma (HCC), and immunotherapy resistance mechanisms are incompletely understood. We report that the E3 ubiquitin ligase Riplet is universally silenced by promoter hypermethylation in HCC. Loss of Riplet modulates fatty acid metabolism to promote terminal exhaustion of CD8 T cells. Riplet loss impedes K48-linked polyubiquitination of fatty acid synthase (FASN), consequently accelerating fatty acid production in HCC. Tumor cell-derived free fatty acids, especially palmitic acid (PA/C16:0), activate STAT3 (signal transducers and activators of transcription 3) by enhancing its palmitoylation in T cells, consequently triggering terminal CD8 T cell exhaustion. HCC cells with Riplet deficiency are resistant to anti-PD-1 therapy, and treatment with an FASN inhibitor overcomes resistance. Our study shows how Riplet can alter lipid metabolism and induce CD8 T cell exhaustion and anti-PD-1 resistance, thus suggesting avenues for combined therapies for treating patients with Riplet-deficient HCC.

DOI: https://doi.org/10.1126/sciimmunol.ado3485
Cancer Lett. 2025 Jun 25. pii: S0304-3835(25)00416-1. [Epub ahead of print] 217849

The significance of protein N-glycosylation in the pathogenesis of lung cancer and its clinical implications.

Yibo Huang, Jin Song, Jinfeng Chen, Feng Li, Yi Zhang, Jing-Hua Yang.

  This comprehensive review systematically elucidates the multifaceted roles of protein N-glycosylation in lung cancer pathogenesis, including its contributions to accelerated cell proliferation, enhanced metastatic potential, promotion of epithelial‒mesenchymal transition (EMT), maintenance of stem cell characteristics, facilitation of immune evasion, preservation of angiogenesis, and diminished drug sensitivity. Additionally, the potential clinical utility of aberrant N-glycosylation is examined as a novel biomarker for early diagnosis, prognostic evaluation, and treatment monitoring in lung cancer. The analysis highlights the critical involvement of N-glycosylation in chemotherapy resistance, targeted therapy, and immunotherapy, offering new perspectives for the development of innovative therapeutic strategies. Furthermore, this review highlights promising applications of antibody-enzyme engineering technology in achieving more precise lung cancer treatments, introducing new opportunities for the field. These findings provide a significant theoretical basis and experimental evidence to support progress in lung cancer research and treatment advancements.

Keywords:  Clinical significance; Fucosylation; Lung cancer; N-Glycosylation; Sialylation

DOI:  https://doi.org/10.1016/j.canlet.2025.217849