bims-cesirm 2025-10-26 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–10–26
twelve papers selected by
Tigist Tamir, University of North Carolina

Global comparative structural analysis of responses to protein phosphorylation.
SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.
The role of fibroblast growth factors in cell and cancer metabolism.
Disrupting mitochondrial β-oxidation by depletion of HADHA impairs primary ciliogenesis.
Revealing the landscape of targeting mitochondrial functions and behaviors to overcome cancer chemoresistance.
Rewiring microbial metabolism through post-translational switches.
Identification of Novel Molecular Subtypes of Prostate Cancer Based on Genes Related to Metabolic Reprogramming to Assess Prognosis and Immune Landscape.
Mitochondrial fatty acid oxidation is stimulated by red light irradiation.
PACT is requisite for prostate cancer cell proliferation.
Enrichment of Cysteine S-palmitoylated peptides using Sodium Deoxycholate Acid Precipitation.
Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.
Isometric representations in neural networks improve robustness.

Nat Commun. 2025 Oct 24. 16(1): 9407

Global comparative structural analysis of responses to protein phosphorylation.

Miguel Correa Marrero, Victor Hugo Mello, Pablo Sartori, Pedro Beltrao.

Post-translational modifications (PTMs), particularly protein phosphorylation, are key regulators of cellular processes, impacting numerous aspects of protein activity. Despite widespread phosphorylation of eukaryotic proteomes, the function of most phosphosites remains unknown. Elucidating the structural mechanisms underlying phosphorylation is crucial for understanding its regulatory roles. Here, we present a comparative structural analysis of phosphorylated and non-phosphorylated proteins taken from the Protein Data Bank (PDB). Our study systematically evaluates how phosphorylation affects backbone conformation, protein dynamics, and mechanical strain. We found that phosphorylation commonly induces small, stabilizing conformational changes through conformational selection and frequently modulates local residue fluctuations, influencing overall protein motion. Notably, a small but significant subset of phosphosites shows mechanical coupling with functional sites, aligning with the domino model of allosteric signal transduction. This work provides a foundation for studying phosphorylation and other PTMs in their structural context, which will guide the rational design of synthetic phosphosites and enable the engineering of PTM-driven regulatory circuits in synthetic biology.

DOI: https://doi.org/10.1038/s41467-025-64116-4
Commun Biol. 2025 Oct 20. 8(1): 1485

SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.

Zhang Xianhong, Gao Yue, Zhang Yu, Zhang Yichen, Chen Yufei, Pei Xinke, Zhang Jinhui, Wang Yiqi, Du Yitian, Hao Shuailin, Ni Ting.

Protein lysine succinylation is a crucial post-translational modification that regulates nearly all aspects of eukaryotic and prokaryotic cell, including gene transcription, cell metabolism and redox homeostasis. Among them, metabolic disorders caused by dysfunctional post-translational modifications induce aging and aged-related diseases, including cancer. This study quantified the dynamic changes in protein succinylation in response to DNA damage stress induced by etoposide (ETOP) in tumor cells. A total of 4354 lysine succinylation sites on 1259 proteins were identified, many of which have not been previously reported. Bioinformatics analysis revealed that many proteins are involved in the metabolism of nicotinamide adenine dinucleotide phosphate (NADPH) in mitochondria (including MTHFD2). We further found that low activity or depletion of MTHFD2 enhances the degree of TIS in breast cancer cells and decreases their resistance to chemotherapeutic agents. Interestingly, we also found that SIRT5-mediated desuccinylation of MTHFD2 was able to reduce the senescence of breast cancer cells, thereby enhancing their resistance to chemotherapeutic drugs. This effect may explain the poorer prognosis observed in breast cancer patients with high expression levels of SIRT5 or MTHFD2. These systematic analyses provide new insights into targeting succinylation-modified metabolic proteins to enhance TIS, and their combination with senolytics for breast cancer therapy.

DOI: https://doi.org/10.1038/s42003-025-08878-z
FEBS Lett. 2025 Oct 23.

The role of fibroblast growth factors in cell and cancer metabolism.

Jessica Price, Chiara Francavilla.

  The fibroblast growth factor (FGF) family and the FGF receptors are ubiquitously expressed and regulate a plethora of cell signaling cascades during development, tissue and cell homeostasis, and metabolism. Dysregulated FGF signaling is associated with cancer and several genetic and metabolic disorders. As FGF signaling regulates all the key metabolic processes to maintain whole-body homeostasis, there is an increasing focus on engineering FGFs as potential treatments for dysregulated metabolism. Within cancer, reprogramming of energy metabolism is a crucial step leading to tumorigenesis, metastasis formation, and resistance to therapy. FGF signaling dysregulation in cancer enables uncontrolled proliferation and survival and promotes therapy resistance and metastasis. However, the role of FGF signaling within cancer metabolism is not well understood. A better understanding of how FGF signaling affects the rewiring of cancer metabolism as well as tumorigenesis would provide novel avenues for discovering potential drug targets and biomarkers. Here, we discuss the role of paracrine, endocrine, and intracellular FGFs within metabolism as well as the current understanding of how FGF signaling contributes to rewired cancer metabolism.

Keywords:  FGF; cancer; cell signaling; fibroblast growth factor receptor; homeostasis; metabolism; metastasis; receptor tyrosine kinase; therapy resistance

DOI:  https://doi.org/10.1002/1873-3468.70199
Sci Rep. 2025 Oct 21. 15(1): 36544

Disrupting mitochondrial β-oxidation by depletion of HADHA impairs primary ciliogenesis.

Joon Bum Kim, Yong Hwan Kim, Seong Hyun Kim, Hyejin Hyung, Jun Hee So, Daeun Park, Na Yeon Park, Dong Kyu Choi, Ji-Eun Bae, Dong-Hyung Cho.

  Primary cilia are dynamic signaling hubs essential for cell homeostasis, and defects in ciliogenesis underpin various genetic disorders. Alpha-hydroxyacyl-CoA dehydrogenase (HADHA), a subunit of the mitochondrial trifunctional enzyme, is crucial for long-chain fatty acid β-oxidation and acetyl-CoA production. Although it was recently demonstrated that lipid metabolism modulates primary ciliogenesis, the connection between mitochondrial β-oxidation and primary cilia remains largely unexplored. Here, we report that HADHA dysfunction markedly impairs primary ciliogenesis and disrupts cilia-dependent signaling. Loss of HADHA reduces both ciliary frequency and length, accompanied by decreased levels of key ciliary signaling mediators. Reintroduction of wild-type HADHA in HADHA knockout cells rescues these defects, whereas its dehydrogenase deficiency mutant (E510Q) fails to restore either normal cilia formation or ciliary signaling. Notably, supplementation with sodium acetate, which resupplies intracellular acetyl-CoA, effectively rescues primary cilium in HADHA-deficient cells. Importantly, this acetate-mediated rescue implicates a potential therapeutic strategy for HADHA-related disorders, supporting the translational relevance of modulating acetyl-CoA levels to restore ciliary function. These findings suggest a relevant link between mitochondrial β-oxidation and primary ciliogenesis, highlighting acetyl-CoA as a potential therapeutic target for disorders related to HADHA deficiency.

Keywords:  Acetyl-CoA; Ciliopathy; HADHA; Primary cilia; β-oxidation

DOI:  https://doi.org/10.1038/s41598-025-18451-7
J Natl Cancer Cent. 2025 Oct;5(5): 453-473

Revealing the landscape of targeting mitochondrial functions and behaviors to overcome cancer chemoresistance.

Haoyan Zhang, Sicheng Wang, Peng Wu, Zanmin Hu, Yani Chen, Yupeng Guan, Jun Pang.

  With the rapid progression of chemotherapies, the occurrence of chemoresistance is becoming a major obstacle in contemporary cancer treatment. As essential organelles, mitochondria perform diverse functions to provide ATP and various intermediates to modulate biosynthetic and bioenergetic processes, which are indispensable to cell survival. Recently, mitochondria have increasingly intrigued researchers for their unique influence on chemoresistance. This review explores the intricate relationship between mitochondria and chemoresistance. We delve into the complex roles that mitochondria play in chemoresistance, focusing on the aberrant alterations in mitochondrial behaviors and interactions with other organelles. We also review the subsequent impact of mitochondrial changes on cellular functions, such as metabolic reprogramming and the dysregulation of cell death. By presenting a retrospective analysis of previous research and elucidating the underlying mechanisms, we aim to reveal the potential of enhancing the efficacy of chemotherapies and overcoming cancer chemoresistance by targeting mitochondria. Hopefully, this review will provide directions for future research and the development of more viable drugs, ultimately improving the prognosis of cancer patients.

Keywords:  Cancer; Chemotherapy; Drug resistance; Mitochondria

DOI:  https://doi.org/10.1016/j.jncc.2025.02.007
Trends Biotechnol. 2025 Oct 23. pii: S0167-7799(25)00409-3. [Epub ahead of print]

Rewiring microbial metabolism through post-translational switches.

Xianhao Xu, Yang Li, Jiaheng Liu, Xueqin Lv, Long Liu.

  Recent advances in post-translational regulatory tools have enabled precise and rapid control of metabolic flux in microbial cell factories. In this review, we systematically summarize current post-translational regulatory tools for modulating the abundance, localization, and activity of key metabolic enzymes. We first discuss protein degradation tags for tunable control of enzyme levels. Then, we discuss spatial regulation through natural and synthetic subcellular compartments. We also highlight emerging approaches for engineering allosteric switches, including computational and de novo design methods. Finally, we outline future directions toward orthogonal, efficient, and cross-species compatible systems. This review provides conceptual and technical insights to guide the development of next-generation post-translational regulatory tools for dynamic metabolic control in microbial cell factories.

Keywords:  allosteric regulation; metabolic flux control; post-translational regulation; protein degradation tags; subcellular compartmentalization

DOI:  https://doi.org/10.1016/j.tibtech.2025.10.002
Crit Rev Eukaryot Gene Expr. 2025 ;35(7): 11-25

Identification of Novel Molecular Subtypes of Prostate Cancer Based on Genes Related to Metabolic Reprogramming to Assess Prognosis and Immune Landscape.

Wentao Fan, Desheng Zhu, Jiawen Zheng, Min Xu.

Prostate cancer (PRAD) progression varies significantly among patients, with metabolic reprogramming linked to oncogenesis and immune response. However, the prognostic and immune-related roles of metabolic reprogramming-related genes (MRGs) in PRAD remain unclear. PRAD transcriptomic, mutation, and clinical data from TCGA were analyzed. WGCNA identified PRAD-associated gene modules. NMF clustering stratified patients into two molecular subgroups. Prognostic MRGs were screened via univariate Cox and LASSO regression. A gene-based prognostic model was established and validated using ROC, PCA, and Kaplan-Meier analyses. A clinical-variable nomogram predicted survival, with external validation via GEO data set GSE70770. Immune traits of subtypes/risk groups were assessed via ESTIMATE, CIBERSORT, and ssGSEA. Drug sensitivity and gene expression (qRT-PCR) were evaluated. Two metabolic subtypes with distinct survival and immune patterns were identified. A four-gene signature (AKR1C2, PITPNM3, PLA2G5, UCK2) formed a prognostic model. Risk stratification revealed groups with divergent survival rates. High-risk patients exhibited poorer outcomes, reduced immune infiltration, and altered drug sensitivity. The MRG prognostic model stratifies PRAD patients by survival and immune landscape, aiding precision immunotherapy and drug discovery.

DOI: https://doi.org/10.1615/CritRevEukaryotGeneExpr.2025060696
FEBS Lett. 2025 Oct 18.

Mitochondrial fatty acid oxidation is stimulated by red light irradiation.

Manuel Alejandro Herrera, Camille C Caldeira da Silva, Maiza Von Denz, Mauricio S Baptista, Alicia J Kowaltowski.

  Keratinocytes are the primary constituents of sunlight-exposed epidermis. In these cells, ultraviolet (UV) A light completely inhibited oxidative phosphorylation, while equivalent doses of blue and green light preserved metabolic fluxes but reduced viability. In contrast, red light enhanced proliferation and elevated basal and maximal oxygen consumption rates for 48 h without altering protein levels of the electron transport chain. Targeted flux analysis revealed that red light specifically activates AMP-activating protein kinase (AMPK)-dependent mitochondrial fatty acid oxidation. This was accompanied by reduced levels of free fatty acids and increased acetyl-CoA carboxylase phosphorylation. Together, our results characterize wavelength-selective regulation of keratinocyte metabolism: UV/visible wavelengths induce damage, while red light triggers AMPK-dependent fatty acid oxidation, providing a mechanistic explanation for photobiomodulation in epidermal cells. Impact statement Sunlight impacts skin cells in surprising ways. While UVA harms energy production and blue/green light reduces survival, red light boosts keratinocyte metabolism. We show that red light activates AMPK-dependent fatty acid oxidation, enhancing proliferation and energy use. These findings reveal how specific wavelengths can damage or stimulate skin cells.

Keywords:  AMPK; beta oxidation; light; metabolism; mitochondria; skin

DOI:  https://doi.org/10.1002/1873-3468.70195
Sci Rep. 2025 Oct 21. 15(1): 36610

PACT is requisite for prostate cancer cell proliferation.

Dianne J Beveridge, Andrew J Woo, Kirsty L Richardson, Rikki A M Brown, Lisa M Stuart, Manjot Singh, Andrew D Redfern, Peter J Leedman.

  PACT (encoded by the PRKRA gene) is a double-stranded RNA binding protein with defined antiviral defense and cytoplasmic RNA-induced silencing actions in mammals. We previously described a further role for PACT as a modulator of nuclear receptor (NR)-regulated gene expression. Here, we investigated the role of PACT in prostate cancer (PCa) using a loss-of-function approach. Depletion of PACT in multiple PCa cell lines resulted in a reduction in cell proliferation, but viability was maintained. RNA-sequencing analysis of LNCaP PCa cells ± PACT revealed a depletion of biological processes involved in cell cycle, mitochondrial function, and NR-response pathways in the PACT knockout (KO) cells. In the PACT KO cells, downregulated genes included the androgen-regulated KLK3 (prostate specific antigen, PSA), together with H2AFJ, PSMD5, AQP3, TMEM45B, and SLC22A3, and siRNA-mediated knockdown of these genes reduced cell growth and proliferation in LNCaP cells. Further, reducing PACT or PSA induced cell cycle arrest at G0/G1. Additionally, the hormone-mediated upregulation and AR antagonist-driven downregulation of PSA gene expression were respectively attenuated and enhanced in PACT KO cells. Taken together, these data support a pro-proliferative role for PACT in PCa, and siRNA therapeutic targeting of PACT, or downregulated genes with PACT KO, could represent a new therapeutic approach.

Keywords:  Cell-cycle; PACT; PSA; Proliferation; Prostate cancer

DOI:  https://doi.org/10.1038/s41598-025-20494-9
Mol Cell Proteomics. 2025 Oct 16. pii: S1535-9476(25)00317-2. [Epub ahead of print] 101218

Enrichment of Cysteine S-palmitoylated peptides using Sodium Deoxycholate Acid Precipitation.

Peter T Jensen, Giuseppe Palmisano, Christopher J Rhodes, Martin R Larsen.

S-palmitoylation is a poorly understood post-translational modification that is gaining more attention as an essential regulator of cellular processes. The reversible nature of S-palmitoylation may allow for fine-tuned control of cellular events and adaptation to stimuli. The detection of S-palmitoylated proteins and peptides includes the Acyl-Biotin Exchange (ABE) method, Acyl resin-assisted Capture (Acyl-RAC), metabolic labelling, and derivatives thereof. We present a novel method of enrichment of S-palmitoylated peptides termed SDC Acid Precipitation Enrichment (SDC-ACE). Here, S-palmitoylated peptides are enriched by taking advantage of their co-precipitation with Sodium-Deoxycholate (SDC) under acidic conditions, allowing easy and fast separation of lipidated peptides from the sample suspension. We initially applied our novel method for the characterization of the mouse brain, providing an in-depth analysis of S-palmitoylation events within the brain and comprehensive profile of the mouse brain S-palmitoylome. Further, we applied our method for mapping mouse tissue-specific S-palmitoylation, highlighting the extensive role of S-palmitoylation throughout various organs in the body. Finally, we applied our methods for studying the brain palmitoylome of diabetic db/db mouse, uncovering alterations in the palmitoylation of proteins associated with obesity and type 2 diabetes. The SDC-ACE method allows fast and easy enrichment of S-palmitoylated peptides, providing a valuable tool for exploring the dynamics and function of S-palmitoylation in diverse biological systems.

DOI: https://doi.org/10.1016/j.mcpro.2025.101218
Sci Rep. 2025 Oct 23. 15(1): 37028

Glutaminase inhibitor CB-839 causes metabolic adjustments in colorectal cancer cells.

Martina Spada, Cristina Piras, Vera Piera Leoni, Mattia Casula, Gabriella Simbula, Antonio Noto, Katia Lilliu, Karolina Krystyna Kopeć, Gabriele Serreli, Federica Murgia, Federica Etzi, Tinuccia Dettori, Luigi Atzori, Paola Caria.

  Colorectal cancer (CRC) cells are 'addicted' to glutamine to satisfy energy and biosynthetic needs. Inhibiting glutamine metabolism enzymes, like glutaminase, is a potential cancer therapy strategy. Although the GLS inhibitor CB-839 is being evaluated in clinical trials, a comprehensive assessment of its antitumor activity in CRC cells is crucial. The present study aimed to evaluate the impact of CB-839 treatment on different CRC cell lines in terms of survival and proliferation. Furthermore, metabolic adaptations resulting from CB-839 treatment, particularly in energetic pathways, were investigated. Three CRC cell lines (HCT116, HT29, and SW480) were treated with different CB-839 concentrations. Cytotoxicity was assessed via MTT assay, proliferation capacity by flow cytometry, and ATP production rates by Seahorse XF analysis. Moreover, metabolomic profile was explored with untargeted GC-MS and 1H-NMR, and targeted analysis of the Krebs cycle was conducted using GC-MS/MS. HT29 cells exhibited the highest sensitivity to CB-839. Subsequent experiments focused on HT29 and SW480 cells. CB-839 treatment altered cell cycle progression and increased glycolytic ATP production in HT29 cells. Metabolomic analysis revealed changes in Krebs cycle and glutaminolysis in both cell lines, along with alterations in amino acids, sugars, antioxidants, and organic acid levels. This study highlighted glutamine's key role in CRC cells and provided a foundation for elucidating the mechanisms of response and resistance to CB-839.

Keywords:  CB-839; Colorectal cancer; Energetic metabolism; Glutaminase-1 inhibition; Glutamine metabolism; Glutaminolysis

DOI:  https://doi.org/10.1038/s41598-025-20528-2
Sci Rep. 2025 Oct 21. 15(1): 36761

Isometric representations in neural networks improve robustness.

Kosio Beshkov, Jonas Verhellen, Mikkel Elle Lepperød.

Artificial and biological agents are unable to learn given completely random and unstructured data. The structure of data is encoded in the distance or similarity relationships between data points. In the context of neural networks, the neuronal activity within a layer forms a representation reflecting the transformation that the layer implements on its inputs. In order to utilize the structure in the data in a truthful manner, such representations should reflect the input distances and thus be continuous and isometric. Supporting this statement, findings in neuroscience propose that generalization and robustness are tied to neural representations being continuously differentiable. Furthermore, representations of objects have the capacity of being hierarchical. Combined together, these two conditions imply that neural networks need to both preserve the distances between inputs as well as have the capacity to apply cuts at different resolutions, corresponding to different levels of a hierarchy. During cross-entropy classification, the metric and structural properties of network representations are usually broken both between and within classes. To achieve and study this behavior, we train neural networks to perform classification while simultaneously maintaining the metric structure within each class at potentially different levels of a hierarchy, leading to continuous and isometric within-class representations. We show that such network representations turn out to be a beneficial component for making accurate and robust inferences about the world. We come up with a network architecture that facilitates hierarchical manipulation of internal neural representations. We verify that our isometric regularization term improves the robustness to adversarial attacks on MNIST and CIFAR10. Finally, we use toy datasets and show that the learned map is isometric everywhere, except around decision boundaries.

DOI: https://doi.org/10.1038/s41598-025-20619-0