bims-cesirm 2025-08-24 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–08–24
fourteen papers selected by
Tigist Tamir, University of North Carolina

Ablation of Hepatocyte Derived-FGL1 Does Not Aggravate Metabolic Dysfunction-Associated Steatotic Liver Disease.
Membrane flexibility induced by BST2 contributes to radioresistance in glioblastoma.
G6PC1 expression as a prognostic biomarker associated with metabolic reprogramming and tumor microenvironment in hepatocellular carcinoma.
IGFBP3-mediated effects of an effective combination therapy on HCC.
NRF2-dependent suppression of selenoprotein P expression promotes intracellular selenium metabolic remodeling and upregulation of antioxidant selenoproteins in hepatocellular carcinoma.
Integrated proteomic and metabolomic profiling identifies distinct molecular signatures and metabolic pathways associated with obesity and potential targets for anti-obesity therapies.
USP44 Regulates Chemoresistance Induced by ROS and the MAPK/NF-κB Pathway Through the Stabilization of ITGB4 in Gastric Cancer.
The dual GLP-1 and GIP receptor agonist tirzapetide provides an unintended interaction with the β-adrenoceptors and plays a role in glucose metabolism in hyperglycemic or senescent cardiac cells.
GATA3 promotes ferroptosis resistance by repressing integrin β1 signaling.
Targeting AXL can effectively overcome c-Met-induced therapeutic resistance in renal cancer and promote tumor cell death through increased oxidative stress.
Phosphoproteome-derived peptide libraries for deep specificity profiling of phosphatases and phospholyases.
O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism.
Molecular stratification of prostate cancer through sensory perception-related multi-omics analysis reveals chemoresistant mechanisms.
Global proteomics reveals distinct muscle adaptations to menstrual cycle phase-based sprint interval training in endurance-trained females.

FASEB J. 2025 Aug 31. 39(16): e70962

Ablation of Hepatocyte Derived-FGL1 Does Not Aggravate Metabolic Dysfunction-Associated Steatotic Liver Disease.

Jean Personnaz, Lisa Cannizzo, Céline Marie Pauline Martin, Aurore Desquesnes, Manon Sotin, Joanna DaSilva, Prunelle Perrier, Hervé Guillou, Léon Kautz.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) begins with simple steatosis, which can progress to hepatocellular carcinoma (HCC). The pathogenesis of MASLD alters the secretion of hepatokines such as fibrinogen-like 1 (FGL1), a candidate mediator of liver steatosis and hyperglycemia. To investigate the contribution of FGL1 to liver diseases, we compared wild-type mice to mice with hepatocyte-specific deletion of Fgl1 subjected to a steatosis or HCC experimental protocol. We found that mice deficient for Fgl1 in hepatocytes showed higher levels of plasma glucose, pronounced metabolic alterations, and liver injury when fed a western diet compared to their wild-type counterparts. However, both genotypes exhibited similar lipid deposition in the liver. Similarly, wild type and Fgl1-deficient mice displayed comparable liver alterations during HCC progression. We observed that FGL1 expression was repressed during MASLD progression in mice and humans concomitantly with the severity of liver injury. Altogether, these findings suggest that FGL1 is not a major contributor to the pathogenesis of MASLD and HCC.

Keywords:  diet; fibrosis; hepatocyte; inflammation; liver cancer; liver injury; metabolism

DOI:  https://doi.org/10.1096/fj.202501997R
Oncogene. 2025 Aug 18.

Membrane flexibility induced by BST2 contributes to radioresistance in glioblastoma.

Haksoo Lee, Dahye Kim, Byeongsoo Kim, Eunguk Shin, Hyunkoo Kang, Jae-Myung Lee, HyeSook Youn, BuHyun Youn.

Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis due to its resistance to radiotherapy. Epidermal growth factor receptor variant III (EGFRvIII), a common mutation in GBM, promotes radioresistance through ligand-independent activation. We hypothesized that membrane flexibility influences EGFRvIII activation and enhances resistance. Bone marrow stromal antigen 2 (BST2, CD317, or TETHERIN) was identified as a key mediator linking membrane dynamics to EGFRvIII-driven survival signaling. Radiation-induced changes in membrane flexibility amplified BST2 activity, stabilizing lipid rafts and promoting EGFRvIII clustering. Pharmacological inhibition of BST2 with arbutin, an FDA-approved compound, disrupted this mechanism, increasing GBM radiosensitivity by enhancing mitochondrial reactive oxygen species (ROS) production and apoptosis. Additionally, BST2 downregulation impaired de novo lipogenesis and reduced lipid droplet accumulation, highlighting its role in metabolic reprogramming. In orthotopic xenograft models, BST2 inhibition suppressed tumor growth and prolonged survival. These findings establish BST2 as a key regulator of membrane-driven radioresistance in GBM. Targeting BST2-mediated membrane remodeling may provide a novel therapeutic strategy to enhance radiotherapy efficacy.

DOI: https://doi.org/10.1038/s41388-025-03544-4
Front Immunol. 2025 ;16 1623315

G6PC1 expression as a prognostic biomarker associated with metabolic reprogramming and tumor microenvironment in hepatocellular carcinoma.

Xilong Tang, Jianjin Xue, Xiao Li, Jie Zhang, Jiajia Zhou.

   Background: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, characterized by a poor prognosis. Many HCC patients are diagnosed at an advanced stage due to the lack of reliable prognostic biomarkers. G6PC1 (Glucose-6-Phosphatase Catalytic Subunit 1) is abnormally expressed in various cancers, including HCC. This study aimed to investigate the biomarker potential and biological functions of G6PC1 to elucidate its impact on HCC pathogenesis.
Methods: G6PC1 expression levels were assessed using TCGA and GEO datasets. Prognostic implications were explored through Kaplan-Meier survival analysis. Potential regulatory transcription factors (TFs) were identified using four prediction tools, and functional mechanisms were investigated via GO and KEGG enrichment analyses. Associations between G6PC1 and HCC metabolic reprogramming, as well as the tumor microenvironment were analyzed.
Results: G6PC1 exhibited low expression levels in HCC, which correlated with poor patient prognosis. HNF4A may act as a regulatory factor for G6PC1 in HCC. Functional analysis identified co-expressed genes associated with metabolism-related pathways. Furthermore, G6PC1 was implicated in metabolic reprogramming, immune infiltration, and immunotherapy response.
Conclusion: Low G6PC1 expression, associated with poor HCC prognosis, is a potential prognostic biomarker. Integrated multi-omics analyses underscore its clinical significance, involvement in metabolic reprogramming, and immunomodulatory functions, providing a foundation for further investigation into its prognostic potential and mechanistic contributions in HCC.

Keywords:  G6PC1; hepatocellular carcinoma; metabolic reprogramming; prognostic biomarker; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1623315
Sci Rep. 2025 Aug 19. 15(1): 28604

IGFBP3-mediated effects of an effective combination therapy on HCC.

Lin Chen, Lei Zhao, Guozhi Wu, Tiantian Zhang, Zhiwu Liu, David Fisher, Nguten Thi Thu Hien, Erkin Musabaev.

  As all known, hepatocellular carcinoma (HCC) accounts for the majority of cases of liver cancer, which is the third leading cause of cancer mortality globally. Moreover, HCC is always accompanied with HBV infection. Here, we used CMAP, a systematic approach for the discovery of functional connections among diseases and drug actions, to identify quercetin as an effective compound to potentially treat HCC. Furthermore, we proved the inhibitory effects of quercetin on HCC cells, shown as decreased cell viability in HCCLM3 and HepG2 cells. In addition, quercetin disturbed the migration of HCC cells in a dose-dependent manner. Furthermore, quercetin treatments effectively elevated the activities of caspase-3 as well as caspase-9 and increased the Bax expression in HCC cells accompanied with decreased levels of p53 and BCL-2, indicating an enhancement of apoptosis induced by quercetin. Notably, quercetin depressed the activities of antioxidant enzymes, including SOD, GST, GPx and CAT, leading to an increase of ROS accumulation. Additionally, quercetin also exhibited an obvious inhibition of tumor growth of HCC in vivo. Through RNA-seq, results showed that genes related to regulation of cell proliferations were enriched, in which IGFBP3 played a critical role in mediating the effects of quercetin on HCC cells by reducing PI3K-mTOR activation. After silencing IGFBP3 in HCCLM3 cells, quercetin exhibited weaken effects on cell proliferation and apoptosis. Notably, IGFBP3 promotor strengthened the suppressed effects induced by single quercetin administration, indicating a potential drug combination for treatments of HCC. Collectively, this study clarified a novel mechanism underlying the inhibitory effects of quercetin on HCC, providing a potential approach for HCC treatment in clinic.

Keywords:  Combination therapy; HCC; IGFBP3; Quercetin; Resveratrol

DOI:  https://doi.org/10.1038/s41598-025-06148-w
Redox Biol. 2025 Aug 13. pii: S2213-2317(25)00334-9. [Epub ahead of print]86 103821

NRF2-dependent suppression of selenoprotein P expression promotes intracellular selenium metabolic remodeling and upregulation of antioxidant selenoproteins in hepatocellular carcinoma.

Kotoko Arisawa, Moeka Natori, Tetta Hiranuma, Misaki Shimizu, Yuto Yamazaki, Yasuhiro Miki, Takashi Toyama, Yoshiro Saito.

Selenium-containing antioxidant enzymes such as glutathione peroxidase 4 (GPx4) and thioredoxin reductase 1 (TrxR1, encoded by TXNRD1) have emerged as therapeutic targets in hepatocellular carcinoma (HCC), a highly treatment-resistant cancer. Hepatocytes play a central role in selenium metabolism by synthesizing and secreting selenoprotein P (SeP, encoded by SELENOP), the major selenium containing protein in plasma, which supplies selenium to peripheral tissues. Although decreased circulating SeP levels have been associated with HCC progression and poor prognosis, the underlying mechanisms remain unclear. In this study, we reanalyzed publicly available single-cell RNA sequence data of HCC tumors and identified a distinct tumor cell cluster characterized by reduced SELENOP expression, enhanced GPX4 and TXNRD1 expression, and activation of NRF2 signaling. In HepG2 cells, pharmacological and genetic activation of NRF2 suppressed SeP expression, elevated TrxR1 levels, and promoted intracellular selenium accumulation. Consistently, SeP knockout (KO) cells exhibited increased intracellular selenium, upregulation of GPx1 and GPx4, and resistance to ferroptosis. Similarly, under selenium-deficient dietary conditions, SeP KO mice showed elevated hepatic selenium and GPx1 expression compared to wild-type controls. These findings uncover a novel NRF2-mediated selenium metabolic remodeling mechanism in HCC, in which SeP suppression promotes intracellular selenium retention and selective upregulation of antioxidant selenoproteins. This redox adaptation contributes to ferroptosis resistance and may represent a potential therapeutic axis in liver cancer.

DOI: https://doi.org/10.1016/j.redox.2025.103821
Front Endocrinol (Lausanne). 2025 ;16 1625501

Integrated proteomic and metabolomic profiling identifies distinct molecular signatures and metabolic pathways associated with obesity and potential targets for anti-obesity therapies.

Yi Li, Huawu Yang, Xinpeng Zhang, Xingyu He, Anke Liuli, Rui Li, Xingyu Han, Yongmei Li, Pan Gao.

   Background: Adipose tissue remodeling induced by bariatric surgery plays a pivotal role in promoting weight loss and metabolic improvement. However, the underlying molecular mechanisms, particularly protein-metabolite regulatory networks, remain poorly understood. This integrative proteomic and metabolomic study identifies key pathway alterations and molecular signatures associated with metabolic phenotypes, offering novel mechanistic insights into the therapeutic efficacy of bariatric surgery.
Methods: Visceral adipose tissue samples were analyzed using label-free DIA quantitative proteomics and LC-MS/MS metabolomics. Proteomic and metabolomic data were processed with MaxQuant software and XCMS R package, respectively.
Results: Proteomic and metabolomic analyses were performed on visceral adipose tissue from 10 obese patients undergoing sleeve gastrectomy and 10 controls. Proteomic profiling quantified identified 135 differentially expressed proteins (57 upregulated, 78 downregulated), with PHACTR2 and PLIN2 upregulated in obesity and ADAR down-regulated in obesity. Enrichment analyses indicated disruptions in lipid droplet formation, muscle processes, and protein autophosphorylation, with KRT1/MYH9 and NF1/ATR identified as hub proteins. Metabolomics revealed 191 differential metabolites (110 upregulated, 81 downregulated), with 4-Vinylcyclohexene positively correlated with BMI and asparagine-betaxanthin negatively correlated. KEGG analysis showed disturbances in purine/pyrimidine metabolism, AMPK signaling, and cortisol biosynthesis. Integrated protein-metabolite network analysis identified OSBPL10, CUL2, and PRTN3 as potential regulators of lipid metabolism and insulin resistance, offering insights into obesity-associated metabolic dysfunction.
Conclusions: This study integrated proteomic and metabolomic data from visceral adipose tissue obtained through sleeve gastrectomy, identifying obesity-related functional pathways and molecular signatures linked to metabolic phenotypes, highlighting the value of multi-omics in understanding adipose tissue remodeling and postoperative metabolic improvement.

Keywords:  adipose tissue; metabolomic; obesity; proteomic; signature

DOI:  https://doi.org/10.3389/fendo.2025.1625501
FASEB J. 2025 Aug 31. 39(16): e70945

USP44 Regulates Chemoresistance Induced by ROS and the MAPK/NF-κB Pathway Through the Stabilization of ITGB4 in Gastric Cancer.

Wanting Xiao, Yuming Lou, Pu Wu, Pengxiang Yang, Hao Wu, Jialu Song, Lutong Liu, Chaoyang Xu.

  Cisplatin (DDP) is a typical chemotherapy agent employed in gastric cancer (GC). Resistance development significantly impairs the success of GC therapy, and the essential mechanisms are not yet fully understood. Deubiquitinase enzymes are pivotal in mediating drug resistance across various cancers via ubiquitin-mediated protein degradation. USP44, a deubiquitinase known as ubiquitin-specific peptidase 44, is implicated in the development of tumors, their spread, and resistance to treatment, although its specific role in gastric cancer has yet to be clarified. We found a significant upregulation of USP44 expression in GC tissues compared to normal tissues, and it serves as a potential indicator of chemotherapy response and survival in GC. Through proteomic analysis, ITGB4 was recognized as a new substrate of USP44. Mechanistically, USP44 stabilizes ITGB4 via deubiquitination, thereby mitigating cisplatin resistance in GC cells by modulating ROS and the MAPK/NF-κB pathway. In addition, ITGB4 affects the expression of P-gp and the activity of antioxidant enzymes through the MAPK/NF-κB pathway, thereby promoting cisplatin efflux and chemoresistance. Our research uncovers a novel mechanism behind cisplatin resistance and indicates that USP44 could be a promising therapeutic target for overcoming cisplatin resistance in gastric cancer patients.

Keywords:  ITGB4; MAPK/NF‐κB signaling pathway; USP44; chemoresistance; gastric cancer; ubiquitylation

DOI:  https://doi.org/10.1096/fj.202501369R
Cardiovasc Diabetol. 2025 Aug 18. 24(1): 338

The dual GLP-1 and GIP receptor agonist tirzapetide provides an unintended interaction with the β-adrenoceptors and plays a role in glucose metabolism in hyperglycemic or senescent cardiac cells.

Dunya Aydos, Zeynep Busra Aksoy, Mehmet Altay Unal, Kamil Can Akcali, Ceylan Verda Bitirim, Belma Turan.

BACKGROUND: A dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1) receptor agonist, tirzepatide (TZPD), is a novel cardioprotective agent, particularly in metabolic disturbances-related co-morbidities, however, there is no exact study to emphasize its possible unintended action in cardiac cells.
OBJECTIVE: Considering a relationship between the trafficking of incretin receptors in a manner not anticipated by the standard way of cAMP as a primary actor in TZPD action, together with the role of cAMP depression in cardiac dysfunction, here, we aimed to elucidate a pattern of unintended receptor interactions of TZPD and molecular processes underlying the pleiotropic effects of TZPD through modulation of the β-adrenoceptors (β-ARs) signaling in cardiomyocytes.
METHODS: To establish the multifaceted cardioprotective function and underlying mechanisms of TZPD against hyperglycemia (HG)-or senescence (SC)-induced cardiac dysfunction, H9c2 cells were treated with and without TZPD. We also used β3-ARs overexpressed H9c2 cells (β3OE) for comparisons.
RESULTS: The TZPD intervention ameliorated the HG or SC phenotypes in the cardiac cells via alleviation in protein levels of GLP-1R and GIP-R as well as production of cAMP or cGMP, even in the presence of these receptor antagonisms. TZPD also increased the levels of β1- and β2-ARs while significantly decreasing activated β3-ARs and PKG, being parallel to normalizations in the cAMP and cGMP in the presence of the antagonisms of these receptors. The therapeutic effects of TZPD on similar parameters of the β3OE group of cells can strongly verify its unintended action among multifaceted effects in either HG or SC cells. In addition, molecular dynamics simulations indicated that TZPD binds with the highest affinity to GLP-1R and β3-ARs rather than GIP-R and then relatively lower but almost similar affinities to β1- and β2-ARs. Furthermore, mechanistically, the cardioprotective effect of TZPD includes significant regulation of the cellular Ca2+, at most, modulating the proteins in β-ARs signaling pathways. Moreover, TZPD could significantly increase not only the depressed protein level but also the translocation of GLUT4 on the sarcolemma, promoting glucose uptake in the HG or SC groups independent of its receptor actions.
CONCLUSIONS: Our findings indicate that TZPD, with its multifaceted role, has beneficial effects on cardiac cells by positively modulating β-ARs signaling and glucose metabolism rather than on-target receptor action. Furthermore, we demonstrated how TZPD can engage the different targets with distinct signaling motifs at the sarcolemma.

DOI: https://doi.org/10.1186/s12933-025-02828-z
Proc Natl Acad Sci U S A. 2025 Aug 26. 122(34): e2427304122

GATA3 promotes ferroptosis resistance by repressing integrin β1 signaling.

Emmet R Karner, Mengdie Wang, Hira Lal Goel, Arthur M Mercurio.

  Understanding mechanisms that determine the response of cells to ferroptotic stress is a timely issue that has significant ramifications for biology and pathology. We investigated these mechanisms in the context of breast cancer where tumors are composed of diverse populations of cancer cells that differ in their ferroptosis sensitivity. Using single-cell RNA-sequencing, we determined that cancer cell populations with luminal differentiation are more resistant to ferroptosis than other cells within a heterogeneous tumor. Subsequent bioinformatic analysis and experimentation revealed that GATA3, a transcription factor that promotes luminal differentiation, has a causal role in ferroptosis resistance in luminal breast cancer cells. In pursuit of the mechanism involved, we found that GATA3 represses the expression of integrin β1 and its downstream signaling cascade. This observation led us to demonstrate that integrin β1 signaling is necessary for sensitivity to ferroptosis in basal breast cancer cells because it regulates a FAK/ROCK pathway that sustains the expression of ACSL4, a lipid-modifying enzyme that is essential for ferroptosis. The repression of integrin β1 by GATA3 inhibits this signaling pathway, rendering cells ferroptosis resistant. Together, these data provide insight into mechanisms of ferroptosis sensitivity and resistance that are linked to the cell biology and signaling pathways of the diverse types of cells present in breast tumors.

Keywords:  GATA3; breast cancer; ferroptosis; integrin; tumor heterogeneity

DOI:  https://doi.org/10.1073/pnas.2427304122
Cancer Lett. 2025 Aug 17. pii: S0304-3835(25)00554-3. [Epub ahead of print] 217984

Targeting AXL can effectively overcome c-Met-induced therapeutic resistance in renal cancer and promote tumor cell death through increased oxidative stress.

Akash Sabarwal, Marc Machaalani, Laxminarayan Rawat, Johannes Wedel, Saba Tabasum, Yuzuru Sasamoto, Florian Buerger, Josie Ascione, Marc Eid, Karl Semaan, Eddy Saad, Yifan Yang, Dongwon Lee, F Stephen Hodi, Matthew L Freedman, Gwo-Shu Mary Lee, Murugabaskar Balan, Toni K Choueiri, Soumitro Pal.

  The mechanisms underlying therapeutic resistance to c-Met/receptor tyrosine kinase (RTK) inhibitors in renal cancer remain unexplored. In renal cell carcinoma (RCC) cells, both AXL and c-Met are highly upregulated. Notably, we found that prolonged treatment with the c-Met/RTK inhibitor, cabozantinib (Cabo), a standard treatment for advanced-stage RCC, markedly increased total c-Met levels and promoted renal cancer cell proliferation. This effect was confirmed not only in vitro but also in murine models and renal tumor tissues from Cabo-treated patients. At lower concentrations (1 nM and 10 nM), Cabo treatment failed to inhibit HGF (c-Met ligand)-induced c-Met phosphorylation. Instead, it further enhanced receptor phosphorylation and downstream signaling events for tumor growth. Additionally, Cabo treatment induced AXL-c-Met association and disrupted the physiological degradation of c-Met. However, inhibition or knockout of AXL could significantly overcome therapeutic resistance to c-Met inhibitor(s). It triggered apoptotic cell death through increased oxidative stress and inhibition of the redox-sensitive transcription factor, Nrf2 and its effector molecule, heme oxygenase-1 (HO-1). We also generated Cabo-resistant RCC cells and observed a marked upregulation of both c-Met and AXL in these cells. Epigenomic profiling revealed significant differences between Cabo-resistant and Cabo-sensitive RCC cells. Importantly, inhibition of AXL either using a potent inhibitor, TP-0903, or through genetic silencing resensitized the resistant cells to Cabo-induced cell death. Together, our findings highlight AXL as a key driver of therapeutic resistance to c-Met inhibitors. A combination therapy targeting both c-Met and AXL in renal cancer could be a promising strategy to overcome the acquired resistance to c-Met inhibitors through increased oxidative stress.

Keywords:  AXL; HO-1; Nrf2; Renal cancer; c-Met; oxidative stress; therapeutic resistance

DOI:  https://doi.org/10.1016/j.canlet.2025.217984
bioRxiv. 2025 Aug 13. pii: 2025.08.12.669978. [Epub ahead of print]

Phosphoproteome-derived peptide libraries for deep specificity profiling of phosphatases and phospholyases.

Katarzyna Radziwon, Laura A Campbell, Lauren E Mazurkiewicz, Sopo Jalalishvili, Izabelle Eppinger, Aanika Parikh, Amy M Weeks.

Protein phosphorylation is dynamically regulated by the opposing activities of phosphowriter enzymes (kinases) and phosphoeraser enzymes (phosphatases and phospholyases). While significant progress has been made toward defining the sequences preferences of kinases, the selectivity of phosphoerasers has not been explored at scale. Here, we develop an experimental platform based on tandem mass spectrometry analysis of phosphoproteome-derived peptide libraries (PhosPropels) to map phosphoeraser activity across thousands of biologically relevant phosphosites. We extract positional residue preferences to rapidly define sequence motifs recognized by eight phosphoerasers spanning diverse species of origin, protein folds, and enzymatic mechanisms. Taking advantage of the throughput of our approach, we profiled 34 variants of the phosphothreonine lyase OspF from Shigella flexneri , uncovering an intrinsic preference for p38 and Erk MAP kinase activation loops and revealing the enzyme residues that influence its selectivity for phosphothreonine. Our results establish a general method for linking phosphorylation sites to the enzymes that remove them, providing a means to dissect a key component of cellular regulatory networks.

DOI: https://doi.org/10.1101/2025.08.12.669978
Nat Commun. 2025 Aug 19. 16(1): 7721

O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism.

Hong Dong, Chenxi Liang, Junjie Zhang, Weidong Wu, Nitesh Kumar, Zihao Liu, Yajun Sun, Zhiwei Liao, Xiaolin Cheng, Yanbao Yu, Yong Zhang, Michael J Holtzman, Jianrong Li, Kymberly M Gowdy, Paul G Thomas, Jovica D Badjic, Anjun Ma, Qin Ma, Jacob S Yount, Shan-Lu Liu, Haitao Wen.

Viral infection induces robust reprogramming of metabolic pathways in host cells. However, whether host metabolic enzymes detect viral components remains unknown. Our group and others previously identified O-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial mediator of the antiviral immune responses. Here, by studying a mouse model with a catalytically impaired OGT, we discover a catalytic activity-independent function of OGT in restraining influenza A virus (IAV) infection in addition to its catalytic activity-dependent effect on MAVS-mediated antiviral immunity. Biochemical studies reveal a critical antiviral effect based on OGT interacting with IAV genomic RNA that requires its N-terminal tetracopeptide repeat-4 motif. This interaction causes the translocation of nuclear OGT to cytosolic lipid droplets (LDs) to destabilize LDs-coating perilipin 2, thereby limiting LDs accumulation and in turn virus replication. In sum, our findings reveal OGT as a multifaceted metabolic sensor that integrates MAVS signaling and lipid metabolism to combat viral infection.

DOI: https://doi.org/10.1038/s41467-025-63085-y
Cell Oncol (Dordr). 2025 Aug 19.

Molecular stratification of prostate cancer through sensory perception-related multi-omics analysis reveals chemoresistant mechanisms.

Shi Li, Ye Tian, Yu Sun, Tian Xu, Wei Wang.

   BACKGROUND: Advanced prostate cancer (PCa) displays significant genetic heterogeneity and therapy resistance, yet the role of sensory perception pathways in its progression remains unclear.
METHODS: We performed an integrative multi-omics analysis of sensory perception-linked mRNAs and lncRNAs from TCGA and scRNA-seq data. Unsupervised consensus clustering defined three molecular subtypes (CS1-CS3). Key biomarkers were validated in patient tissues and serum. Immune and stromal infiltration were quantified using TIDE and ESTIMATE. Single-cell trajectories characterized TSC22D3-positive T cells, and NicheNet mapped ligand-receptor interactions.
RESULTS: Three subtypes emerged, with CS1 showing the poorest prognosis, marked chemotherapy resistance, and pronounced stromal-immune crosstalk. CS1 tumors exhibited elevated B- and T-cell infiltration and increased oxidative phosphorylation in TSC22D3-positive T cells. NicheNet analysis identified the TNF-CCL20 axis as a central mediator of immunosuppressive signaling and chemoresistance in CS1.
CONCLUSIONS: This study establishes sensory perception-associated molecular subtypes in PCa and links CS1 chemoresistance to immune microenvironment reprogramming via TNF-CCL20 signaling. These findings offer mechanistic insights into PCa progression and suggest actionable targets to overcome therapeutic resistance.

Keywords:  Chemoresistance; Molecular subtypes; Multi-omics; Prostate cancer; Sensory perception genes; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13402-025-01099-w
Mol Cell Proteomics. 2025 Aug 14. pii: S1535-9476(25)00152-5. [Epub ahead of print] 101053

Global proteomics reveals distinct muscle adaptations to menstrual cycle phase-based sprint interval training in endurance-trained females.

Julie Kissow, Kamine Julie Jacobsen, Søren Jessen, Laura Bachmann Thomsen, Júlia Prats Quesada, Jens Bangsbo, Atul Shahaji Deshmukh, Morten Hostrup.

  Advances in mass-spectrometry (MS)-based technologies have leveraged our understanding of protein-wide adaptations in human skeletal muscle in response to exercise. However, there is a lack of such data in females, particularly pertaining to already trained females and menstrual cycle phase-based sprint interval training (SIT) despite its efficacy and popularity. Here, we present a comprehensive global proteome analysis of skeletal muscle adaptations to high-frequency SIT during different menstrual cycle phases in endurance-trained females. We randomized 49 eumenorrheic females to either high-frequency SIT in the follicular (FB) or luteal phase (LB) over one menstrual cycle comprising eight sessions of 6×30-s all-out efforts. MS-proteomics, covering 4155 proteins after filtering, revealed notable differences in muscle adaptations to phase-based SIT. LB suppressed mitochondrial pathways of the tricarboxylic acid cycle and electron transport chain while enriching ribosomal complexes. Conversely, FB enriched filament organization and skeletal system development. Mitochondrial repression during LB was linked to reduced V˙O2max, whereas exercise capacity improved in FB only. Our findings show that menstrual cycle phase-based high-frequency SIT induces distinct protein-wide muscle adaptations and affects phenotype in endurance-trained eumenorrheic females. CLINICAL TRIAL REGISTRATION NUMBER: NCT04136457.

Keywords:  Athletes; Estrogen; Exercise; Female; Performance; Sex hormones

DOI:  https://doi.org/10.1016/j.mcpro.2025.101053