bims-cesirm 2025-12-14 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–12–14
nine papers selected by
Tigist Tamir, University of North Carolina

Emerging Roles of Post-Translational Modifications in Metabolic Homeostasis and Type 2 Diabetes.
High-fat diet induced ECM remodeling attenuates chemosensitivity in prostate cancer via activating Piezo1-dependent mitochondria-ER contacts.
Mass spectrometry-based profiling of single-cell histone post-translational modifications to dissect chromatin heterogeneity.
Protein CoAlation is regulated by and integrated with growth factor signalling and the cellular antioxidant response.
Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction.
Cysteine Restriction Induces Ferroptosis Depending on the S-adenosylmethionine and Polyamine Biosynthetic Pathways in Hepatic Cancer Cells.
YY1: Master regulator of metabolic reprogramming in cancer.
Quantitative Proteomics of Nitrosylated Proteins in Melanoma Using the Biotin-Switch Technique Combined With Tandem Mass Tag Labeling.
GPMassSimulator: A Graphormer-Based Method for Glycopeptide MS/MS Spectra Prediction.

Int J Mol Sci. 2025 Nov 28. pii: 11552. [Epub ahead of print]26(23):

Emerging Roles of Post-Translational Modifications in Metabolic Homeostasis and Type 2 Diabetes.

Yong Kyung Kim, Hyeongseok Kim.

  Post-translational modifications (PTMs) provide an integrated regulatory layer that couples nutrient and hormonal signals to whole-body energy homeostasis across metabolic organs. PTMs modulate protein activity, localization, stability, and metabolic networks in a tissue- and state-specific manner. Through network remodeling, PTMs integrate receptor signaling with chromatin and organelle function and align transcriptional control with mitochondrial function, proteostasis, and membrane trafficking. PTM crosstalk connects kinase cascades, nutrient-sensing pathways, and ubiquitin-family modifiers to orchestrate gluconeogenesis, lipolysis, glucose uptake, thermogenesis, and insulin secretion in response to nutrient cues. The metabolic state regulates PTM enzymes through changes in cofactors, redox tone, and compartmentalization, and PTM-dependent changes in transcription and signaling feedback to metabolic tone. In obesity and diabetes, dysregulated post translational modification networks disrupt insulin receptor signaling, disturb organelle quality control, and impair beta cell function, which promotes insulin resistance and beta cell failure. Consequently, PTMs organize metabolic information flow and modulate tissue responses to overnutrition and metabolic stress. A systems-level understanding of PTMs clarifies mechanisms of whole-body energy homeostasis and supports the discovery of new therapeutic targets in metabolic disease.

Keywords:  diabetes mellitus; insulin sensitivity; metabolic disorder; post-translational modification

DOI:  https://doi.org/10.3390/ijms262311552
Cancer Lett. 2025 Dec 09. pii: S0304-3835(25)00776-1. [Epub ahead of print] 218204

High-fat diet induced ECM remodeling attenuates chemosensitivity in prostate cancer via activating Piezo1-dependent mitochondria-ER contacts.

Yupeng Guan, Fei Cao, Yusheng Luo, Jun Li, Peng Wu, Junfu Zhang, Wenhan Qiu, Shaohong Lai, Hanqi Lei, Jun Pang.

  High-fat diet (HFD) and obesity are established risk factors for therqpy resistance in prostate cancer (PCa), but the underlying mechanisms remain incompletely understood. Here, we demonstrate that a HFD promote chemoresistance by remodeling the tumor microenvironment (TME) and activating extracellular matrix (ECM)-dependent mitochondria-endoplasmic reticulum contacts (MERCs). Through integration of clinical data with multi-omics and biomechanical analyses, we show that lipid-overloaded tumor cells secrete TGF-β1 to indirectly drive the activation of cancer-associated fibroblasts (CAFs). This triggers pathological ECM stiffening and collagen deposition. These biomechanical alterations are sensed by the mechanosensor Piezo1, which transduces pro-malignant signals that foster chemoresistance. Pharmacological inhibition of Piezo1 blocks its channel activity, disrupts intracellular ion homeostasis and consequently induces MERCs dissociation.. MERCs disassembly, in return, destabilizes the IP3R-GRP75-VDAC complex, leading to metabolic reprogramming characterized by mitochondrial dysfunction, endoplasmic reticulum stress, and redox imbalance. Crucially, dual targeting of lipid metabolism (with statins) and mechanotransduction (with GsMTx4) resensitizes PCa to chemotherapy by normalizing ECM architecture and restoring MERCs integrity. Our work defines the "mechanometabolic niche" as a targetable signaling hub where coordinated lipid metabolism and TME biomechanics converge to dictate therapeutic response and unveils a novel co-targeting strategy for advanced PCa.

Keywords:  chemoresistance; high-fat diet; matrix stiffness; mitochondria-endoplasmic reticulum contacts; piezo1

DOI:  https://doi.org/10.1016/j.canlet.2025.218204
Nat Commun. 2025 Dec 12. 16(1): 11100

Mass spectrometry-based profiling of single-cell histone post-translational modifications to dissect chromatin heterogeneity.

Ronald Cutler, Laura Corveleyn, Claudia Ctortecka, Francesca LiCausi, Joshua Cantlon, Alvaro Sebastian Vaca Jacome, Dieter Deforce, Jan Vijg, Maarten Dhaenens, Malvina Papanastasiou, Steven A Carr, Simone Sidoli.

Single-cell proteomics confidently quantifies cellular heterogeneity, however quantification of post-translational modifications, such as those deposited on histone proteins, remains elusive. Here, we develop a robust mass spectrometry-based method for the unbiased analysis of single-cell histone post-translational modifications (sc-hPTM). sc-hPTM identifies both single- and combinatorial histone post-translational modifications (67 peptidoforms in total), which includes nearly all frequently studied histone post-translational modifications with comparable reproducibility to traditional bulk experiments. As a proof of concept, we treat cells with sodium butyrate, a histone deacetylase inhibitor, and demonstrate that our method can i) distinguish between treated and untreated cells, ii) identify sub-populations of cells with heterogeneous response to the treatment, and iii) reveal differential co-regulation of histone post-translational modifications in the context of drug treatment. The sc-hPTM method enables comprehensive investigation of chromatin heterogeneity at single-cell resolution and provides a further understanding of the histone code.

DOI: https://doi.org/10.1038/s41467-025-66031-0
Redox Biol. 2025 Dec 04. pii: S2213-2317(25)00475-6. [Epub ahead of print]89 103962

Protein CoAlation is regulated by and integrated with growth factor signalling and the cellular antioxidant response.

Donagh Gribbon, Arnau Garcíal Salmerón, Ivan Gout, Rosemary O'Connor.

  Coenzyme A (CoA) is an essential cellular cofactor and low molecular weight thiol (LMWT) that forms metabolically active thioesters involved in various metabolic pathways. Recently, CoA has emerged as an important antioxidant due to its covalent attachment to protein cysteine thiols in response to oxidative and metabolic stress. This modification, termed CoAlation, protects proteins from over-oxidation and can alter protein activity, subcellular localisation and conformation in eukaryotic and prokaryotic cells. However, whether protein CoAlation is implicated in cellular transformation or adaptation to oxidative stress in cancer cells is unknown. Cancer cells are known to harbour high basal reactive oxygen species (ROS) levels and to mitigate oxidative stress by deploying antioxidant enzymes and LMWTs, such as glutathione. Here we investigated whether CoAlation is a component of antioxidant responses in cancer cells. We found that protein CoAlation is detectable at basal levels and is also induced by oxidative stress in a range of cancer cell lines. Interestingly, much of this CoAlation occurs at the mitochondria. Levels of protein CoAlation can be modulated by inhibiting CoA and glutathione biosynthesis and are dependent on both cellular CoA and ROS levels. Deprivation of serum increases oxidative stress-induced protein CoAlation, indicating the requirement for growth and survival factors in antioxidant responses. In line with this, cells that are deficient in Insulin-like Growth Factor 1 (IGF-1) Receptor expression have higher ROS levels, express lower levels of antioxidant proteins, and have elevated levels of protein CoAlation. Overall, we conclude that protein CoAlation is an important arm of the antioxidant response, which is strongly integrated with and regulated by growth factor signalling and the broader antioxidant response.

Keywords:  Antioxidant response; Cancer; Growth factor signalling; IGF-1R; Protein CoAlation; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2025.103962
Aging Cell. 2025 Dec 10. e70318

Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction.

Chung-Yang Yeh, Alexis L Borgelt, Brynn J Vogt, Alyssa A Clark, Ted T Wong, Isaac Grunow, Michelle M Sonsalla, Reji Babygirija, Yang Liu, Michaela E Trautman, Mariah F Calubag, Bailey A Knopf, Fan Xiao, Dudley W Lamming.

  Caloric restriction (CR) extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketone bodies, we investigated the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2, the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remained robust in mice lacking Hmgcs2. To gain insight into why the deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice initiated a CR diet. Surprisingly, as mice adapt to CR, they no longer engage in high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long-term CR are not mediated by ketogenesis.

Keywords:  BHB; caloric restriction; dietary restriction; ketogenesis; ketones; metabolic health; metabolism

DOI:  https://doi.org/10.1111/acel.70318
Gastro Hep Adv. 2026 ;5(2): 100817

Cysteine Restriction Induces Ferroptosis Depending on the S-adenosylmethionine and Polyamine Biosynthetic Pathways in Hepatic Cancer Cells.

Keisuke Tada, Kazuki Mitsuyama, Hironari Nishizawa, Hiroki Shima, Akihiko Muto, Motoshi Wada, Daisuke Saigusa, Kazuhiko Igarashi.

   Background and Aims: Liver diseases such as hepatocellular carcinoma are known to be affected by nutrition and metabolic activities, but the mechanisms behind them remain unclear. We aimed to reveal the relationship between the concentration of sulfur-containing amino acids and hepatocellular response, and further investigated the mechanism focusing on methionine adenosyltransferase, which plays the central role in methionine metabolism by synthesizing S-adenosylmethionine (SAM).
Methods: Mouse hepatoma Hepa1 cells were cultured in media with reduced amounts of cysteine, methionine, or both. Cell death was monitored using propidium iodide and annexin V staining followed by flow cytometry. Metabolites were measured by mass spectrometry. Inhibitors of ferroptosis (Fer-1), necroptosis (GSK872), SAM synthesis (cycloleucine), or polyamine synthesis (sardomozide and difluoromethylornithine) were used.
Results: Cysteine restriction induced marked cell death, whereas simultaneous restriction of cysteine and methionine fully suppressed the cell death. Cysteine restriction-induced cell death was suppressed with Fer-1 and GSK872, suggesting the involvement of ferroptosis in this process. Cysteine restriction decreased reduced glutathione, which was rescued by simultaneous restriction of cysteine and methionine. Cysteine restriction-induced cell death was also suppressed by knockdown of MAT2A or its inhibitor cycloleucine. Furthermore, inhibitors of several enzymes in the polyamine biosynthetic pathway also suppressed the cell death. In contrast, primary culture of mouse hepatocytes did not show cell death upon cysteine restriction.
Conclusion: These results suggest that cysteine-glutathione and SAM-polyamine metabolic pathways are critical modulators of ferroptosis of hepatic cancer cells. Since normal liver cells were more resistant to ferroptosis than cancer cells, cysteine restriction may be exploited in treating hepatic cancer by inducing ferroptosis specifically in cancer cells without affecting normal cells in the liver.

Keywords:  Cysteine; Ferroptosis; Hepatoma; Methionine; S-adenosylmethionine

DOI:  https://doi.org/10.1016/j.gastha.2025.100817
Biochim Biophys Acta Rev Cancer. 2025 Dec 05. pii: S0304-419X(25)00247-1. [Epub ahead of print]1881(1): 189505

YY1: Master regulator of metabolic reprogramming in cancer.

Rimsha Akram, Rendy Hosea, Fuqiang Zhao, Andrzej Górecki, Małgorzata Figiel, Shourong Wu, Vivi Kasim.

  Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to fulfill increased bioenergetic and biosynthetic demands for survival and proliferation. These adaptations arise directly from oncogenic mutations or indirectly via adaptive responses to nutrient scarcity. In addition to supporting survival and biomass production, these metabolic shifts are closely associated with changes in gene expression, cellular differentiation, and the tumor microenvironment, thereby contributing to tumorigenesis and progression. Importantly, the recognition of metabolic dysregulation as a hallmark of malignancy revealed novel avenues for therapeutic intervention, as disrupting these pathways may impair energy generation and biosynthetic processes essential for tumor proliferation. In this review, we integrate data indicating that the transcription factor Yin yang 1 (YY1) is a central regulator of oncogenic metabolic reprogramming. Yin yang 2 (YY2) is a paralog of YY1 and performs distinct role in metabolism and redox regulation. Mechanistically, YY1 enhances aerobic glycolysis by diverting glycolytic flux toward lactate production. Furthermore, it modulates hepatic lipid homeostasis via direct transcriptional control of lipogenic enzymes and crosstalk with nutrient-sensing signaling cascades. Additionally, YY1 rewires amino acid metabolism to fuel tumorigenesis by supplying macromolecules and enabling epigenetic remodeling. Collectively, these findings highlight the equilibrium between YY1 and its paralog YY2 in sustaining redox homeostasis and tumor progression while positioning YY1 as a metabolic checkpoint that dynamically regulates these processes. Understanding these pathways will support development of YY1-directed inhibitors and combinatorial therapies to modulate metabolic reprogramming in cancer.

Keywords:  Amino acids metabolism; Glucose metabolism; Lipid metabolism; Metabolic reprogramming; Tumorigenesis; Yin yang 1 (YY1)

DOI:  https://doi.org/10.1016/j.bbcan.2025.189505
Bio Protoc. 2025 Dec 05. 15(23): e5535

Quantitative Proteomics of Nitrosylated Proteins in Melanoma Using the Biotin-Switch Technique Combined With Tandem Mass Tag Labeling.

Vipin K Yadav, Bin Fang, John M Koomen, Jyoti Srivastava, Sanjay Premi.

  Protein S-nitrosylation is a critical post-translational modification that regulates diverse cellular functions and signaling pathways. Although various biochemical methods have been developed to detect S-nitrosylated proteins, many suffer from limited specificity and sensitivity. Here, we describe a robust protocol that combines a modified biotin-switch technique (BST) with streptavidin-based affinity enrichment and quantitative mass spectrometry to detect and profile nitrosylated proteins in cultured cells. The method involves blocking free thiols, selective reduction of nitrosothiols, biotin labeling, enrichment of biotinylated proteins, and identification by tandem mass tag (TMT)-based quantitative mass spectrometry. Additionally, site-directed mutagenesis is employed to generate "non-nitrosylable" mutants for functional validation of specific nitrosylation sites. This protocol provides high specificity, quantitative capability, and versatility for both targeted and global analysis of protein nitrosylation. Key features • Specific thiol blocking and labeling: Free thiols are blocked with N-ethylmaleimide, followed by selective reduction and biotinylation of S-nitrosothiols for precise nitrosylation detection. • Quantitative proteomics: TMT-labeling with high-resolution LC-MS/MS enables multiplexed, accurate quantification and comprehensive nitrosylome profiling with faster data acquisition and fewer missing values than label-free proteomics. • Functional mutagenesis: Site-directed mutagenesis of cysteine residues generates "non-nitrosylable" mutants to study nitrosylation's impact on protein function. • Versatile application: The protocol is adaptable for both targeted protein analysis and global nitrosylation profiling across diverse cell types and experimental conditions. This protocol is used in: Cancer Research (2025), DOI: 10.1158/0008-5472.CAN-24-0693.

Keywords:  Biotin-Switch Technique; Liquid chromatography–tandem mass spectrometry (LC–MS/MS); Protein S-nitrosylation; Quantitative proteomics; Site-directed mutagenesis; Streptavidin affinity enrichment; Tandem mass tag (TMT) labeling; Thiol blocking

DOI:  https://doi.org/10.21769/BioProtoc.5535
Anal Chem. 2025 Dec 09.

GPMassSimulator: A Graphormer-Based Method for Glycopeptide MS/MS Spectra Prediction.

Yihui Ren, Dongbo Bu, Bo Duan, Chunming Zhang, Bin Cong, Shiwei Sun.

Protein glycosylation is a critical post-translational modification involved in numerous biological processes and disease states. While mass spectrometry has emerged as the primary tool for glycoproteomics analysis, the structural complexity and heterogeneity of glycopeptides pose significant analytical challenges. Existing glycopeptide identification tools primarily rely on mass matching, underutilizing intensity information from mass spectra, which limits their ability to discriminate between similar glycopeptides (glycopeptides bearing analogous glycans/peptide backbones). Here we present GPMassSimulator, an innovative deep learning framework for accurate prediction of intact N-glycopeptide tandem mass spectrometry (MS/MS) spectra and retention time. GPMassSimulator employs the GpepFormer module to effectively represent and integrate both peptide sequences and glycan structures, capturing their complex dependencies. The integrated representation is then passed through the Prediction module to generate the theoretical MS/MS spectra and the retention time of the glycopeptides. Our method demonstrated an outstanding performance on the benchmark set. In the experiment distinguishing similar glycan compositions, GPMassSimulator achieved an identification accuracy of 97.1%. Furthermore, in distinguishing isomeric structures, our method achieved more accurate Top-1 identifications than the current approaches. Additionally, the rescoring experiment on pGlyco3 highlighted the significant improvement in the sensitivity of our model for glycopeptide identification. These excellent results showcased the promising potential of our approach in glycoproteomics.

DOI: https://doi.org/10.1021/acs.analchem.5c02375