bims-cesirm 2025-08-17 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–08–17
nine papers selected by
Tigist Tamir, University of North Carolina

The insulin signalling network.
Protein modifications by advanced glycation end products (AGEs) in human clear cell renal cell carcinoma.
Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.
Receptor Tyrosine Kinase Profiling Identifies Chronic Constitutive Floodgate Oxidative Signaling in Glutathione-Independent Human Mammary Luminal Progenitor Cells.
High-fat circulating nutrients promote growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer.
Quinolinic Acid Protects Mouse Liver from High-fat Diet Induced MASLD by Inhibiting Lipid Uptake Gene Expression.
p53 Modulates the Gut-Liver Axis via PI3K/AKT/Wnt Signaling Pathways in Type 2 Diabetes.
Pharmacological but Not Physiological Levels of GDF15 and FGF21 Regulate Body Weight and Glycemic Control in Obese Mice.
O-GlcNAcylation of PRDX1 enhances its stability and promotes liver cancer progression via activating LRP6-mediated Wnt signaling.

Nat Metab. 2025 Aug 11.

The insulin signalling network.

James G Burchfield, Alexis Diaz-Vegas, David E James.

Insulin signalling is a central regulator of metabolism, orchestrating nutrient homeostasis and coordinating carbohydrate, protein and lipid metabolism. This network operates through dynamic, tightly regulated protein phosphorylation events involving key kinases such as AKT, shaping cellular responses with remarkable precision. Advances in phosphoproteomics have expanded our understanding of insulin signalling, revealing its intricate regulation and links to disease, particularly cardiometabolic disease. Major insights, such as the mechanisms of AKT activation and the influence of genetic and environmental factors, have emerged from studying this network. In this Review, we examine the architecture of insulin signalling, focusing on its precise temporal regulation. We highlight AKT's central role in insulin action and its vast substrate repertoire, which governs diverse cellular functions. Additionally, we explore feedback and crosstalk mechanisms, such as insulin receptor substrate protein signalling, which integrates inputs through phosphorylation at hundreds of distinct sites. Crucially, phosphoproteomics has uncovered complexities in insulin-resistant states, where network rewiring is characterized by disrupted phosphorylation and the emergence of novel sites that are absent in healthy cells. These insights redefine insulin signalling and its dysfunction, highlighting new therapeutic opportunities.

DOI: https://doi.org/10.1038/s42255-025-01349-z
J Transl Med. 2025 Aug 14. 23(1): 914

Protein modifications by advanced glycation end products (AGEs) in human clear cell renal cell carcinoma.

Agnieszka Gęgotek, Justyna Brańska-Januszewska, Paweł Samocik, Robert Kozłowski, Mariusz Koda, Neven Zarkovic, Elżbieta Skrzydlewska, Halina Ostrowska.

   BACKGROUND: The development of cancer is often associated with altered glycolytic processes, resulting in the accumulation of highly reactive dicarbonyl compounds that promote protein modifications through advanced glycation end products (AGEs). This study aimed to quantify and identify the major AGE-modified proteins in clear cell renal cell carcinoma (ccRCC).
METHODS: A proteomic approach (SDS-PAGE/HPLC/MS-MS) with partial validation based on 2D-SDS-PAGE-Western blot was used to identify protein modifications by AGEs in cancer tissue samples of 16 patients with ccRCC compared to respective non-tumor kidney tissues of the same patients.
RESULTS: The findings revealed elevated levels of carboxymethylation/carboxyethylation along with the increased formation of pyrraline, argpyrimidine, and pentosidine on cysteine, lysine, or arginine residues in tumor tissues compared to matched non-tumor kidney tissue. Albumin was identified as a target for AGE modifications in its pre-proalbumin and mature forms. Most of the AGE-modified proteins in ccRCC tissues were involved in catalytic and binding functions, regulation, transcription and transport. These proteins were distributed throughout the cell, including the nucleus, as confirmed by immunofluorescence analysis. Of note, five of ten AGE-modified glycolytic enzymes were found exclusively in ccRCC tissues.
CONCLUSIONS: This study demonstrates a distinct AGE-modified proteome in ccRCC compared to non-tumor tissue, with modifications frequently occurring within or near functional domainst. Therefore, further investigation into the mechanisms underlying AGE-protein adduct formation in renal carcinogenesis could help in understanding ccRCC development.

Keywords:  Advanced glycation end products (AGEs); Clear cell renal cell carcinoma (ccRCC); Kidney disease; Protein modification; Proteomics; Tumor

DOI:  https://doi.org/10.1186/s12967-025-06958-6
Nat Commun. 2025 Aug 14. 16(1): 7570

Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.

Qinqin Ouyang, Jiaqi Su, Yixuan Li, Haiping Liao, Haiying Guo, Yanan Sun, Xiaoyu Wang, Juan Chen, Josephine Thinwa, Wen-Xing Ding, Herbert Tilg, Fazheng Ren, Hao Zhang, Rong Liu.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are two common liver disorders characterized by abnormal lipid accumulation. Our study found reduced levels of GTPase-activating protein-binding protein1 (G3BP1) in patients with MASLD and MASH, suggesting its involvement in these liver disorders. Hepatocyte-specific G3BP1 knockout (G3BP1 HKO) male mice had more severe MASLD and MASH than their corresponding controls. Intriguingly, the G3BP1 HKO MASLD model male mice exhibit dysregulated autophagy, and biochemical analyses demonstrated that G3BP1 promotes autophagosome-lysosome fusion through direct interactions with the SNARE proteins STX17 and VAMP8. We also show that hepatic knockout of G3BP1 promotes de novo lipogenesis, and ultimately found that G3BP1 is required for the nuclear translocation of the well-known liver-lipid-regulating transcription factor TFE3. Taken together, our results suggest that G3BP1 should be investigated as a potential target for developing medical interventions to treat MASLD and MASH.

DOI: https://doi.org/10.1038/s41467-025-63022-z
bioRxiv. 2025 Jul 18. pii: 2025.07.15.665005. [Epub ahead of print]

Receptor Tyrosine Kinase Profiling Identifies Chronic Constitutive Floodgate Oxidative Signaling in Glutathione-Independent Human Mammary Luminal Progenitor Cells.

Syed Musheer Mohammed Aalam, Megan L Ritting, Hari Ps, Geng-Xian Shi, Kingsley Shih, Yifei Dong, Guruprasad Kalthur, Cao Miao, Yifan Yu, David Jhf Knapp, Peter Eirew, Davide Pellacani, Chitra Priya Emperumal, Hequn Wang, Jeffrey R Janus, Mark E Sherman, Mathew P Goetz, Sarah A McLaughlin, Judy C Boughey, Amy C Degnim, Haishan Zeng, Akilesh Pandey, Derek C Radisky, Anguraj Sadanandam, Nagarajan Kannan.

The human mammary epithelium contains a subset of luminal progenitor (LP) cells that are distinct from basal cells in both lineage potential and redox biology. LPs are uniquely equipped to tolerate oxidative stress through glutathione-independent mechanisms and have been implicated as candidate cells of origin in basal-like breast cancers. In this study, we identify the receptor tyrosine kinase (RTK) cKIT (CD117), as a defining feature of LPs and a key mediator of their expansion. cKIT is developmentally restricted to the LP compartment via Polycomb-mediated epigenetic repression in basal and luminal-committed cells. It is expressed in scattered epithelial cells within both ductal and alveolar regions of resting human mammary glands. Using RTK-engineered MCF10A models, we demonstrate that cKIT ligand/stem cell factor (SCF)-activated wildtype cKIT signaling is sufficient to drive proliferation in the absence of epidermal growth factor (EGF) and that cKIT is responsive not only to canonical ligands but also to hydrogen peroxide (H₂O₂). In primary human LPs, cKIT is rapidly phosphorylated upon exposure to SCF and H₂O₂, with concomitant AKT activation. These responses are enhanced when cKIT and EGFR signaling are co-engaged, suggesting a cooperative mitogenic program. In mammary gland, phosphorylation of the antioxidant enzyme PRDX1 is selectively detected in LPs, consistent with a floodgate model of redox signaling in which transient oxidative inactivation of peroxiredoxins (PRDXs) facilitates RTK signaling under elevated intracellular reactive oxygen species conditions. Clinically, elevated cKIT expression is associated with shorter progression-free survival in certain basal-like breast cancer, supporting a link between LP-like redox signaling states and aggressive tumor behavior. Together, these findings define a redox-integrated RTK signaling axis centered on cKIT that drives LP expansion and is associated with poor outcomes in a subset of basal breast cancers. This work establishes a mechanistic framework for targeting redox-responsive progenitor populations in both regenerative and oncologic context.

DOI: https://doi.org/10.1101/2025.07.15.665005
bioRxiv. 2025 Jul 16. pii: 2025.07.10.664224. [Epub ahead of print]

High-fat circulating nutrients promote growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer.

Maryam Kohram, Carolina Trenado-Yuste, Molly C Brennan-Smith, Evelyn S Navarro Salazar, Pengfei Zhang, Jasmine E Hao, Xincheng Xu, Bharvi Chavre, William Oh, Sherry X Zhang, Susan E Leggett, Rolf-Peter Ryseck, Joshua D Rabinowitz, Celeste M Nelson.

Diet influences the levels of small molecules that circulate in plasma and interstitial fluid, altering the biochemical composition of the tumor microenvironment (TME). These circulating nutrients have been associated with how tumors grow and respond to treatment, but it remains difficult to parse their direct effects on cancer cells. Here, we combine a three-dimensional (3D) microfluidic tumor model with physiologically relevant culture media to investigate how concentrations of circulating nutrients influence tumor growth, cancer cell invasion, and overall tumor metabolism. Human triple-negative breast cancer cells cultured in 2D under media conditions mimicking five different dietary states show no observable differences in proliferation or morphology. Nonetheless, those exposed to high-fat conditions exhibit increased metabolic activity and upregulate genes associated with motility and extracellular matrix remodeling. In the 3D microfluidic model, high-fat conditions accelerate tumor growth and invasion and induce the formation of hollow cavities. Surprisingly, the presence of these cavities does not correlate with an increase in apoptosis or ferroptosis. Instead, RNA-sequencing analysis revealed that high-fat conditions induce the expression of MMP1 , consistent with cavitation via cell invasion. Mimicking the flow of circulating nutrients within the TME can thus be used to identify novel connections between metabolic states and tumor phenotype.

DOI: https://doi.org/10.1101/2025.07.10.664224
Eur J Pharmacol. 2025 Aug 13. pii: S0014-2999(25)00819-2. [Epub ahead of print] 178065

Quinolinic Acid Protects Mouse Liver from High-fat Diet Induced MASLD by Inhibiting Lipid Uptake Gene Expression.

Bao Wang, Delong Zhen, Jin Wei, Lina Ding, Wenyu Ding, Bernard Portha, Junjun Liu.

  Quinolinic acid (QA) is a metabolite of tryptophan catabolism involved in the biosynthesis of nicotinamide adenine dinucleotide (NAD). It has been extensively studied in the context of neuropsychiatric disorders in the past decades. Recent studies have also linked high plasma QA levels to obesity, metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetes. In the present study, we have explored the impact of long-term oral QA administration on glucose and lipid metabolism in mice. We observed a protective role for QA in preventing hepatic lipid accumulation in high-fat-diet fed mice, whereas oral administration of NAD showed opposite effects. We further demonstrated that QA reduces hepatic lipid uptake by inhibiting the expression of lipoprotein lipase (LPL) and fatty acid translocase (CD36) in liver, thereby mitigating liver lipid accumulation in the context of a high-fat diet. Our data suggest that QA is an important regulator of lipid homeostasis and has potential as a therapeutic target for MASLD.

Keywords:  CD36; LPL; Liver; MASLD; NAD; Quinolinic acid

DOI:  https://doi.org/10.1016/j.ejphar.2025.178065
FASEB J. 2025 Aug 31. 39(16): e70898

p53 Modulates the Gut-Liver Axis via PI3K/AKT/Wnt Signaling Pathways in Type 2 Diabetes.

Qiang Li, Lei Zhang, Yuhan Sun, Zhaoyang Du, Shoulong Xu, Xuejing Wang, Shanshan Wei, Yinan Tao, Bin Li, Jing Jiang, Guangfu Di, Yanjiao Huang, Zhiliang Xu.

  The p53 protein has been identified as a critical regulator of metabolic processes in a variety of diseases, including obesity, diabetes, liver disease, and cardiovascular disease. However, the precise function and mechanism of action of p53 in the regulation of glucose-lipid metabolism through the enterohepatic axis remain to be fully elucidated. The present study investigated the effects of p53 deficiency on type 2 diabetic mice and demonstrated that p53 deficiency resulted in more severe impairment of glucose tolerance and insulin tolerance. Furthermore, the study revealed that p53 can influence hepatic glucose metabolism via the PI3K/AKT pathway. Additionally, p53 deletion has been observed to modify intestinal function and the intestinal microenvironment, thereby correlating with intestinal function and microbiota composition in T2DM mice. Specifically, p53 knockout mice exhibited impaired ileal digestion, absorption, and colonic secretion after a HFD (HFD). Additionally, the richness and diversity of their intestinal microbiota were reduced, and these mice exhibited symptoms such as obesity, fat infiltration, defecation abnormalities, and severe abnormalities of glucose and insulin tolerance. The expression levels of β-catenin and c-Myc proteins were found to be elevated in mice fed a HFD, while the expression of these proteins was diminished in mice with p53 knockout, compared to those on a normal diet. The experimental results suggest that p53 affects insulin secretion through the PI3K/AKT signaling pathway and regulates the distribution of intestinal microbiota through the Wnt signaling pathway, which in turn affects the development of type 2 diabetes mellitus.

Keywords:  WntAkt/PI3K; intestinal microbiota; p53; type 2 diabetes

DOI:  https://doi.org/10.1096/fj.202500755RR
FASEB J. 2025 Aug 15. 39(15): e70918

Pharmacological but Not Physiological Levels of GDF15 and FGF21 Regulate Body Weight and Glycemic Control in Obese Mice.

Sarah Engelbeen, Julie Mie Jacobsen, Luisa Deisen, Elisa Parsche, Alberte Buch-Ramussen, Christoffer Clemmensen, Rune Ehrenreich Kuhre, Kornelia Johann, Maximilian Kleinert.

  GDF15 and FGF21 are stress-induced hormone-like factors with putative roles in the regulation of energy homeostasis. Since their plasma levels increase with obesity, it has been proposed that GDF15 and FGF21 jointly impose a cap on weight gain during diet-induced obesity. To test this hypothesis, we generated single Gdf15 knockout (KO) and Fgf21 KO, and double Gdf15/Fgf21 KO mice. Depletion of both GDF15 and FGF21 had minimal effects on the gain of body weight, fat, and fat-free mass in male or female mice fed either chow diet or high-fat, high-sucrose diet. Similarly, glucose tolerance, fasting glucose, and plasma insulin levels were largely unaffected by the combined absence of GDF15 and FGF21. Thus, combined deletion of endogenous Gdf15 and Fgf21 exerted a limited influence on body weight gain or glycaemic control. By contrast, pharmacological dosing of obese male mice with long-acting recombinant GDF15 or FGF21 produced meaningful weight loss on their own (8%-10%), and GDF15 + FGF21 co-administration yielded an impressive, additive weight reduction of 25%. Combinatorial treatment also improved glucose tolerance, lowered fasting insulin levels, and reduced hepatic fat content. In conclusion, while endogenous GDF15 and FGF21 appear largely nonessential for the regulation of weight gain and glycemia, pharmacological co-treatment with GDF15 and FGF21 elicits robust weight-loss benefits.

Keywords:  FGF21; GDF15; diet‐induced obesity; energy homeostasis regulation; gene knockout mice; glucose tolerance; pharmacological weight‐loss therapy

DOI:  https://doi.org/10.1096/fj.202501350R
Cell Signal. 2025 Aug 07. pii: S0898-6568(25)00470-X. [Epub ahead of print]135 112055

O-GlcNAcylation of PRDX1 enhances its stability and promotes liver cancer progression via activating LRP6-mediated Wnt signaling.

Luo Dai, Zheng Xu, Yin Fan, Wei Gao, Guandou Yuan, Songqing He, Linfeng Mao.

   BACKGROUND: O-GlcNAcylation, a post-translational modification intricately implicated in oncogenic processes, has garnered significant attention as a potential therapeutic target in cancer biology. Peroxiredoxin 1 (PRDX1), a master regulator of reactive oxygen species (ROS) homeostasis and antioxidant defense systems, is increasingly recognized for its contributory role in the pathogenesis of diverse malignancies. However, the functional significance of PRDX1 in liver cancer pathogenesis and the mechanistic underpinnings of its regulation remain to be fully elucidated.
METHODS: In our preliminary investigations, we identified PRDX1 as a substrate amenable to O-GlcNAcylation via immunoprecipitation-mass spectrometry (IP-MS) profiling. Western blotting was performed to determine the levels of PRDX1 and O-GlcNAcylation in liver cancer tissues. Colony formation, scratch test, transwell assay and nude mouse tumor model assays were used to determine the roles of PRDX1 and O-GlcNAcylation in liver cancer progression. IP-MS was used to screen the interacting protein LRP6 of PRDX1, cycloheximide (CHX) chase assay, ubiquitination test were used to determine the stability, proximity ligation assay (PLA), immunofluorescent staining (IF) were performed the O-GlcNAcylation of PRDX1.
RESULTS: Herein, we demonstrate that PRDX1 exerts profound oncogenic effects, driving liver cancer progression in both in vitro and in vivo experimental models. Notably, we reveal that PRDX1 undergoes pronounced O-GlcNAcylation in liver cancer, a modification that enhances its protein stability by attenuating ubiquitin-proteasomal degradation. Furthermore, PRDX1 interacts with low-density lipoprotein receptor-related protein 6 (LRP6), stabilizing its expression and subsequently activating the canonical Wnt/β-catenin signaling cascade.
CONCLUSION: Our findings suggest that O-GlcNAcylation stabilizes PRDX1, promoting liver cancer progression. PRDX1-LRP6 interaction activates Wnt/β-catenin signaling, driving tumorigenesis. Targeting the O-GlcNAcylation-PRDX1-LRP6 axis holds therapeutic promise.

Keywords:  LRP6; Liver cancer; O-GlcNAcylation; PRDX1; Wnt pathway

DOI:  https://doi.org/10.1016/j.cellsig.2025.112055