bims-cesirm 2025-08-10 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–08–10
twelve papers selected by
Tigist Tamir, University of North Carolina

NADH reductive stress drives metabolic reprogramming.
HCF-1 as a key modulator of OGT function and O-GlcNAcylation in the liver.
Post-Translational Modifications Remodel Proteome-Wide Ligandability.
AND-1 is a critical regulator of R-loop dynamics and a target to overcome endocrine resistance.
Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.
Regulator of G-protein signaling 2 as a Suppressor of Sphingosine-1-phosphate 2- and 3-mediated Signaling in Colon Cancer Cells.
Post-translational modifications of Stat3: The state of the art.
Investigation of ribociclib, abemaciclib and palbociclib resistance in ER+ breast cancer cells reveal potential therapeutic opportunities`.
Phosphofructokinase-1 redefined: a metabolic hub orchestrating cancer hallmarks through multi-dimensional control networks.
Three-Dimensional Network of Creatine Metabolism: from Intracellular Energy Shuttle to Systemic Metabolic Regulatory Switch.
Distinct lipidomic profiles in breast cancer cell lines relate to proliferation and EMT phenotypes.
Pro-inflammatory cytokines as regulators of protein tyrosine phosphatases and insulin signaling in murine skeletal muscle cells.

Trends Cell Biol. 2025 Aug 05. pii: S0962-8924(25)00157-6. [Epub ahead of print]

NADH reductive stress drives metabolic reprogramming.

Ronghui Yang, Zihao Guo, Binghui Li.

  Cellular metabolism is intricately regulated by redox signaling, with the NADH/NAD+ couple serving as a central hub. Emerging evidence reveals that NADH reductive stress, marked by NADH accumulation, is not merely a passive byproduct of metabolic dysfunction but an active regulatory signal driving metabolic reprogramming. In this Review, we synthesize recent advances in understanding NADH reductive stress, including its origins, regulatory mechanism, and manipulation. We examine its broad impact on cellular metabolism, its interplay with oxidative and energy stress, and its pathogenic roles in a range of diseases. By integrating these findings, we propose NADH reductive stress as a master regulator for metabolic reprogramming and highlight new avenues for mechanistic exploration and therapeutic intervention.

Keywords:  NADH reductive stress; NADH-reductive-stress-associated diseases; energy stress; metabolic reprogramming; oxidative stress

DOI:  https://doi.org/10.1016/j.tcb.2025.07.005
Sci Rep. 2025 Aug 03. 15(1): 28328

HCF-1 as a key modulator of OGT function and O-GlcNAcylation in the liver.

Vaibhav Kapuria, Ayushma, Winship Herr, Shilpi Minocha.

  Host cell factor-1 (HCF-1) is a transcriptional coregulator essential for maintaining liver function and cellular metabolism. O-linked N-acetylglucosamine transferase (OGT) is a key nutrient-sensing enzyme that catalyzes protein O-GlcNAcylation, a critical post-translational modification regulating metabolic pathways. This study investigates the role of hepatocyte-specific depletion of HCF-1 in regulating OGT stability, activity, and cellular localization in hepatocytes. Using a transgenic mouse model with hepatocyte-specific HCF-1 deletion, we assessed the impact of HCF-1 loss on OGT expression and O-GlcNAcylation activity. OGT protein levels, mRNA expression, and cellular localization were evaluated using molecular and histological techniques. Comparisons were made with control mice and hepatocytes under nutrient-starved conditions. Hepatocyte-specific HCF-1 deletion led to progressive loss of HCF-1 protein and a concomitant decrease in OGT levels and global O-GlcNAcylation. Loss of HCF-1 did not alter OGT mRNA levels, suggesting post-translational regulation. Immunofluorescence revealed reduced nuclear OGT and O-GlcNAcylation, mimicking changes observed under fasting conditions. Isolated HCF-1-deficient hepatocytes showed impaired adhesion, further underscoring HCF-1's role in hepatocyte function. Notably, in heterozygous Hcfc1hepKO/ + females, HCF-1-negative hepatocytes displayed cytoplasmic O-GlcNAcylation, while HCF-1-positive cells maintained nuclear localization. HCF-1 is crucial for regulating OGT stability, activity, and nuclear localization in hepatocytes. These findings establish a mechanistic link between HCF-1 and OGT, highlighting their coordinated role in hepatic nutrient sensing and metabolic regulation.

Keywords:   O-GlcNAcylation; O‐linked N‐acetylglucosamine (O‐GlcNAc) transferase (OGT); Hepatocytes; Host cell factor-1; Liver; Nutrient sensing.

DOI:  https://doi.org/10.1038/s41598-025-11813-1
bioRxiv. 2025 Aug 02. pii: 2025.07.31.667978. [Epub ahead of print]

Post-Translational Modifications Remodel Proteome-Wide Ligandability.

Weichao Li, Qijia Wei, Paolo Governa, Manuel Llanos, Tzu-Yuan Chiu, Jacob M Wozniak, Appasso M Jadhav, Clara Gathmann, Jacob Cravatt, Ashok Dongre, Mia L Huang, Stefano Forli, Christopher G Parker.

Post-translational modifications (PTMs) vastly expand the diversity of human proteome, dynamically reshaping protein activity, interactions, and localization in response to environmental, pharmacologic, and disease-associated cues. While it is well established that PTMs modulate protein function, structure, and biomolecular interactions, their proteome-wide impact on small-molecule recognition-and thus druggability-remains largely unexplored. Here, we introduce a chemical proteomic strategy to delineate how PTM states remodel protein ligandability in human cells. By deploying broad profiling photoaffinity probes, we identified over 400 functionally diverse proteins whose ability to engage small molecules is impacted by phosphorylation or N-linked glycosylation status. Integration of binding site mapping with structural analyses revealed a diverse array of PTM-dependent pockets. Among these targets, we discovered that the phosphorylation status of common oncogenic KRAS mutants impact the action of small molecules, including clinically approved inhibitors. These findings illuminate an underappreciated, PTM-governed layer of proteome plasticity and uncover opportunities for the development of chemical probes to selectively target proteins in defined modification states.

DOI: https://doi.org/10.1101/2025.07.31.667978
Sci Adv. 2025 Aug 08. 11(32): eadv2453

AND-1 is a critical regulator of R-loop dynamics and a target to overcome endocrine resistance.

Zhuqing Li, Yihan Peng, Huai-Chin Chiang, Yanjun Gao, Chen Chu, Yi Zhang, Muhammad Jameel Mughal, Chengyu Liu, Rong Li, Huadong Pei, Wenge Zhu.

R-loops are three-stranded DNA/RNA hybrids that are essential for various cellular pathways. However, when dysregulated, they lead to genomic instability and numerous human diseases. R-loops are tightly regulated, with RNase H1 acting as a key enzyme responsible for resolving DNA/RNA hybrids. Here, we identify the DNA-binding protein AND-1 as an essential factor in R-loop regulation through directly binding to R-loop structures, where it enhances the recruitment of RNase H1 and stimulates its endonuclease activity. We also provide in vivo evidence that R-loop accumulation occurs in the mammary gland tissue of AND-1-deficient mice. Furthermore, we demonstrate that inhibition of AND-1 decreases ESR1 expression by disrupting R-loop regulation at the enhancer region of the ESR1 gene in estrogen receptor-positive (ER+) breast cancer cells, thereby overcoming resistance to aromatase inhibitors. Collectively, our findings reveal a mechanism by which AND-1 modulates R-loop dynamics and present a promising therapeutic strategy to combat endocrine resistance in breast cancer.

DOI: https://doi.org/10.1126/sciadv.adv2453
bioRxiv. 2025 Jul 24. pii: 2025.07.23.666448. [Epub ahead of print]

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.

Milan R Savani, Bailey C Smith, Wen Gu, Yi Xiao, Gerard Baquer, Bingbing Li, Skyler S Oken, Namya Manoj, Lauren G Zacharias, Vinesh T Puliyappadamba, Sylwia A Stopka, Michael S Regan, Michael M Levitt, Charles K Edgar, William H Hicks, Soummitra Anand, Tracey Shipman, Misty S Martin-Sandoval, Rainah Winston, João S Patrício, Xandria Johnson, Trevor S Tippetts, Diana D Shi, Andrew Lemoff, Timothy E Richardson, Pascal O Zinn, Ashley Solmonson, Thomas P Mathews, Nathalie Y R Agar, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.

Conventional stable isotope tracing assays track one or several metabolites. However, cells use an array of nutrients to sustain nitrogen metabolic pathways. This incongruency hampers a system level understanding of cellular nitrogen metabolism. Therefore, we created a platform to simultaneously trace 30 nitrogen isotope-labeled metabolites. This platform revealed that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine despite expressing de novo pathway enzymes. This link between cell state and pyrimidine synthesis routes persisted in physiological contexts, including primary murine and human tissues and tumor xenografts. Mechanistically, we found that Ser1900 phosphorylation of CAD, the first enzyme of the de novo pathway, was enriched in primitive cells and that mimicking this modification in differentiated cells abrogated their preference for pyrimidine salvage. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.

DOI: https://doi.org/10.1101/2025.07.23.666448
J Biol Chem. 2025 Aug 01. pii: S0021-9258(25)02405-6. [Epub ahead of print] 110554

Regulator of G-protein signaling 2 as a Suppressor of Sphingosine-1-phosphate 2- and 3-mediated Signaling in Colon Cancer Cells.

Jaejun Eo, Nahyun Kim, Sungho Ghil.

  Sphingosine-1-phosphate receptor 2 (S1P2) and S1P3 are G protein-coupled receptors that mediate extracellular sphingosine-1-phosphate (S1P) signaling into cells. S1P2 and S1P3 are highly expressed in colon cancer cells, but their roles in cancer progression-related cellular phenotypes are not well understood. Recent studies suggest that RGS2 interacts with GPCRs, either directly or indirectly, to regulate their signaling. However, the precise role of RGS2 in S1P2 and S1P3 signaling remains uninvestigated. In this study, we examined the interaction of RGS2 with S1P2 and S1P3 using BRET analysis and assessed its impact on S1P2- and S1P3-mediated signaling in 293T and HCT116 cells. BRET analysis revealed that RGS2 and Gα subunits simultaneously bind to S1P2 and S1P3. Furthermore, in the presence of these receptors, RGS2 translocated from the cytoplasm to the cell membrane. These interactions and membrane translocation were not observed with the RGS1 negative control, highlighting the specificity of RGS2 for S1P2 and S1P3. RGS2 expression inhibited the activation of Gαi, Gαq, and Gα12, key signaling pathways mediated by S1P2 and S1P3. S1P2 and S1P3 activation significantly enhanced cell migration and the expression of cancer-associated genes, effects that were effectively suppressed by RGS2 expression. In contrast, RGS1 failed to inhibit S1P2- and S1P3-mediated Gα signaling, as well as downstream effects such as enhanced cell migration and cancer-associated gene expression. Our findings show that RGS2 suppresses S1P2- and S1P3-mediated cancer-associated cellular phenotypes by interacting with these receptors and inhibiting Gα-mediated signaling.

Keywords:  Bioluminescence resonance energy transfer; Gα subunits; membrane translocation; tumor progression

DOI:  https://doi.org/10.1016/j.jbc.2025.110554
Cell Signal. 2025 Aug 07. pii: S0898-6568(25)00463-2. [Epub ahead of print]135 112048

Post-translational modifications of Stat3: The state of the art.

Jiaxu Chen, Caiyun Mao, Ning Han, Qi Zhou, Chenhao Feng, Xutao Sun, Yunjia Song.

  Signal transducer and activator of transcription 3 (Stat3), a critical transcription factor, plays an essential role in cellular processes such as proliferation, development, and differentiation. It also significantly contributes to the pathogenesis of cardiovascular diseases and various cancers, including breast cancer, pancreatic cancer, and renal cell carcinoma. The functional dynamics of Stat3 are intricately regulated by post-translational modifications (PTMs) such as phosphorylation, sulfenylation, acetylation, sulfhydrylation, and SUMOylation. These modifications, triggered by pathophysiological signals, induce structural changes in Stat3 across different cell types, thereby regulating distinct gene expression programs. Such modifications can either enhance or inhibit Stat3's transcriptional activity and affect its DNA-binding stability. This review explores the various PTMs that modulate Stat3 function, offering a comprehensive analysis of the regulatory mechanisms that govern Stat3 within cellular signaling networks. The findings are expected to provide valuable insights into the development of novel therapeutic agents targeting these pathways, ultimately revealing new targets and innovative strategies for treating a range of diseases.

Keywords:  Acetylation; Methylation; Phosphorylation; Post-translational modifications; Stat3; Sulfenylation; Sulfhydrylation

DOI:  https://doi.org/10.1016/j.cellsig.2025.112048
Sci Rep. 2025 Aug 05. 15(1): 28579

Investigation of ribociclib, abemaciclib and palbociclib resistance in ER+ breast cancer cells reveal potential therapeutic opportunities`.

Mashael Algethami, Ahmed Shoqafi, Ayat Lashen, Shatha Alqahtani, Jake Spicer, Ahmad ALtayyar, Çağla Tosun, Jennie N Jeyapalan, Nigel P Mongan, Victoria James, Emad A Rakha, Srinivasan Madhusudan.

  The cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) ribociclib, abemaciclib, and palbociclib have transformed outcomes in patients with ER+ /HER2 - advanced breast cancer (BC). However, most patients eventually progress, and therapeutic options beyond CDK4/6i are an area of ongoing investigation. Here, we generated and evaluated ribociclib, abemaciclib, and palbociclib-resistant BCs. MCF7 and T47D (ER+ /HER2-) cells were chronically treated with increasing doses of ribociclib (R), abemaciclib (A), or palbociclib (P) over 8 months (0-600 nM). CDK4/6i-resistant cell lines (MCF7rR, MCF7rA, MCF7rP, T47DrR, T47DrA, and T47DrP) were isolated and evaluated for their aggressive phenotypes, cross-resistance, transcriptomic changes, and sensitivity to volasertib (PLK1 inhibitor) and barasertib (AukB inhibitor). Immunohistochemical evaluation of CDK4, CDK6, and p53 (n = 1005) and transcriptomic evaluation of AukB and PLK1 were performed in 5031 clinical breast cancers. MCF7rR, MCF7rA, MCF7rP, T47DrR, T47DrA, and T47DrP cells manifested aggressive phenotypes such as increased spheroid formation, invasion, proliferation, and progression through the G1/S phase of the cell cycle despite CDK4/6i treatment, increased resistance to apoptosis, and cross-resistance to other CDK4/6i. Transcriptomic analysis revealed the enrichment of distinct pathways in resistant cells, particularly the upregulation of cell cycle regulatory genes such as PLK1, AukB, CDKN2B and TGFβ. PLK1 or AukB overexpressing resistant cells were sensitive to volasertib (PLK1 inhibitor) and barasertib (AukB inhibitor) therapy, which was associated with G2/M cell cycle arrest and increased apoptosis. We conclude that cell cycle upregulation leading to G2/M progression is a key route for CDK4/6i resistance. AukB or PLK1 inhibitors that block G2/M phase could be a promising strategy.

Keywords:  Abemaciclib; Breast cancer; CDK4; CDK6; Mechanism of resistance; Palbociclib; Ribociclib

DOI:  https://doi.org/10.1038/s41598-025-11052-4
J Transl Med. 2025 Aug 06. 23(1): 873

Phosphofructokinase-1 redefined: a metabolic hub orchestrating cancer hallmarks through multi-dimensional control networks.

Rong Yuan, Junqi Wang, Shengkang Zhang, Zhaojun Xu, Lan Song.

  Phosphofructokinase-1 (PFK-1), the core rate-limiting enzyme of glycolysis, has transcended its classical metabolic regulatory role and emerged as a multi-dimensional hub in tumour biology. This review systematically delineates the dynamic regulatory networks of PFK-1 isoforms (PFKP, PFKL, PFKM) in cancer: epigenetic remodelling drives tissue-independent expression reprogramming; post-translational modification networks confer metabolic-signalling dual functions; and the dynamic nature of its subcellular localization facilitates noncanonical roles, such as intranuclear transcriptional regulation. These mechanisms collectively orchestrate hallmark oncogenic processes, including tumour proliferation, metastatic invasion, cell death evasion, angiogenesis, immune escape, and metabolic reprogramming. In clinical translation, PFK-1 isoform expression profiles, modification states, and subcellular dynamics exhibit robust correlations with cancer diagnosis, prognosis, and therapeutic response. The isoform-specific modification networks unveil novel targets for developing diagnostic biomarkers and tissue-selective therapeutic strategies. This work not only reestablishes the central role of PFK-1 in tumour metabolic plasticity but also offers a fresh perspective for overcoming cancer treatment challenges.

Keywords:  Cancer; Clinical translation; Glycolysis; Isoform; Mechanism; Phosphofructokinase-1

DOI:  https://doi.org/10.1186/s12967-025-06897-2
Mol Metab. 2025 Aug 06. pii: S2212-8778(25)00135-8. [Epub ahead of print] 102228

Three-Dimensional Network of Creatine Metabolism: from Intracellular Energy Shuttle to Systemic Metabolic Regulatory Switch.

Yuhui Su.

   BACKGROUND: Creatine serves as an intracellular shuttle for high-energy phosphate bonds, enabling rapid ATP transfer from energy-producing to energy-consuming cellular compartments. In skeletal muscle, creatine coordinates energy distribution among mitochondrial oxidative phosphorylation, glycolysis, and the phosphagen system. Consequently, creatine supplementation acutely enhances muscular performance and is widely utilized as an ergogenic aid in power-based sports. Recent studies demonstrate that enhanced creatine metabolism in adipose tissue promotes brown adipocyte renewal and boosts energy expenditure in cold environments or sedentary conditions, thereby improving overall systemic metabolism. Beyond its traditional role as an exercise supplement, the creatine metabolic network has emerged as a promising therapeutic target for metabolic disorders.
SCOPE OF REVIEW: This review begins by revisiting the history and latest advancements in creatine research, and ultimately proposes three dimensions for the current explanation of creatine metabolism: (1) subcellular energy transport; (2) muscle-fat metabolic axis; (3) systemic energy sensing and metabolic reprogramming.
MAJOR CONCLUSIONS: The creatine cycle enables directed energy flow through mitochondrial supercomplexes (VDAC/ANT-CK) and resets systemic metabolism via subcellular energy tunnels and inter-organ interactions. Creatine kinase (CK) condensates, through liquid-liquid phase separation, can rapidly meet energy demands during exercise. Therefore, targeting the dynamics of the CK phase may be promising for enhancing athletic performance and improving metabolic diseases.

Keywords:  Creatine; Energy metabolism; Exercise; Metabolic diseases; Phase separation; Thermogenesis

DOI:  https://doi.org/10.1016/j.molmet.2025.102228
Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Aug 03. pii: S1388-1981(25)00087-3. [Epub ahead of print] 159679

Distinct lipidomic profiles in breast cancer cell lines relate to proliferation and EMT phenotypes.

Hanneke Leegwater, Zhengzheng Zhang, Xiaobing Zhang, Xuesong Wang, Thomas Hankemeier, Annelien J M Zweemer, Bob van de Water, Erik Danen, Menno Hoekstra, Amy C Harms, Alida Kindt, Sylvia E Le Dévédec.

  Rewiring of lipid metabolism is a hallmark of cancer, supporting tumor growth, survival, and therapy resistance. However, lipid metabolic heterogeneity in breast cancer remains poorly understood. In this study, we systematically profiled the lipidome of 52 breast cancer cell lines using liquid chromatography-mass spectrometry to uncover lipidomic signatures associated with tumor subtype, proliferation, and epithelial-to-mesenchymal (EMT) state. A total of 806 lipid species were identified and quantified across 21 lipid classes. The main lipidomic heterogeneity was associated with the EMT state, with lower sphingolipid, phosphatidylinositol and phosphatidylethanolamine levels and higher cholesterol ester levels in aggressive mesenchymal-like cell lines compared to epithelial-like cell lines. In addition, cell lines with higher proliferation rates had lower levels of sphingomyelins and polyunsaturated fatty acid (PUFA) side chains in phospholipids. Next, changes in the lipidome over time were analyzed for three fast-proliferating mesenchymal-like cell lines MDA-MB-231, Hs578T, and HCC38. Triglycerides decreased over time, leading to a reduction in lipid droplet levels, and especially PUFA-containing triglycerides and -phospholipids decreased during proliferation. These findings underscore the role of EMT in metabolic plasticity and highlight proliferation-associated lipid dependencies that may be exploited for therapeutic intervention. In conclusion, our study reveals that EMT-driven metabolic reprogramming is a key factor in lipid heterogeneity in breast cancer, providing new insights into tumor lipid metabolism and potential metabolic vulnerabilities.

Keywords:  Breast cancer; Cancer metabolism; Cell line panels; Epithelial to mesenchymal transition; Lipidomics

DOI:  https://doi.org/10.1016/j.bbalip.2025.159679
Cell Signal. 2025 Jul 31. pii: S0898-6568(25)00452-8. [Epub ahead of print] 112037

Pro-inflammatory cytokines as regulators of protein tyrosine phosphatases and insulin signaling in murine skeletal muscle cells.

Vanessa Stein, Peter Geserick, Katharina Friedrich, Björn Brinschwitz, Isabell Marie Musal, Jannis Ulke, Jens Fielitz, Kai Kappert.

  Inflammatory processes can disrupt tissue homeostasis and promote metabolic disturbances, including insulin resistance. Pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), mediate this process. Since skeletal muscle is one of the major insulin-sensitive tissues, it is crucial to search for molecular links that promote insulin resistance during inflammation. Protein tyrosine phosphatases (PTPs) negatively regulate insulin signaling in multiple organs and models. To gain insight into the potential interactions of cytokines and PTPs in skeletal muscle, we characterized the effects and kinetics of cytokine stimulation on insulin signaling in murine C2C12 muscle cells. The protein level and activities of PTP non-receptor type 1 (PTPN1/PTP1B) and type 2 (PTPN2/TCPTP) were evaluated after cytokine stimulation and addressed by pharmacological inhibition or siRNA-mediated knockdown (KD). TNF, IL-1β and IL-6 elicited different kinetics and expression patterns of the respective PTPs and insulin signaling molecules, while surprisingly, insulin action was preserved. Furthermore, PTPN1 and PTPN2 had only minor effects on insulin signaling in C2C12 cells with siRNA-mediated compensatory PTP regulation. However, pan-PTP inhibition by sodium orthovanadate confirms that PTPs are negative regulators of insulin signaling. In summary, our data provide insights into the balance of the physiological and pathophysiological effects of cytokines and targeting individual PTPs to regulate insulin signaling in C2C12 cells. Additionally, our findings highlight the complex dynamics and interplay of cytokines, PTPs and metabolic pathways. This should be acknowledged when new therapeutic tools are developed to address inflammation-induced diseases such as type 2 diabetes or related comorbidities.

Keywords:  Insulin signaling; Muscle cells; Pro-inflammatory cytokines; Protein tyrosine phosphatase, non-receptor type 1 (PTPN1); Protein tyrosine phosphatase, non-receptor type 2 (PTPN2); Protein tyrosine phosphatases (PTPs)

DOI:  https://doi.org/10.1016/j.cellsig.2025.112037