bims-cesirm 2025-07-13 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2025–07–13
nine papers selected by
Tigist Tamir, University of North Carolina

HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.
Abnormal β-Hydroxybutyrylation Modification of ARG1 Drives Reprogramming of Arginine Metabolism to Promote the Progression of Colorectal Cancer.
Fatty acid synthase-derived lipid stores support breast cancer metastasis.
USP44 promotes chemotherapeutic drug resistance of triple negative breast cancer through EZH2 protein stability.
DNA2 protein destruction dictates DNA hyperexcision, cGAS-STING activation, and innate immune response in CDK12-deregulated cancers.
Metabolic hallmarks of trastuzumab resistance.
Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer.
Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.
Identifying Links between Alzheimer's Disease and Type 2 Diabetes through Proteomics.

Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2504080122

HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.

Amy M Ehrlich, Kirstin A MacGregor, Stephen P Ashcroft, Lewin Small, Ali Altıntaş, Alexander V Chibalin, Matthias Anagho-Mattanovich, Ben Stocks, Thomas Moritz, Jonas T Treebak, Juleen R Zierath.

  The regulation of metabolism in peripheral tissues is intricately linked to circadian rhythms, with hypoxia-inducible factor-1α (HIF1α) implicated in modulating time-of-day-specific exercise responses. To investigate this relationship, we generated a skeletal muscle-specific HIF1α knockout (KO) mouse model and performed extensive metabolic phenotyping and transcriptomic profiling under both basal conditions and following acute exercise during early rest (ZT3) and active (ZT15) phases. Our findings reveal that HIF1α drives a more robust transcriptional and glycolytic response to exercise at ZT3, promoting glucose oxidation and mannose-6-phosphate production while potentially sparing fatty acid oxidation. In the absence of HIF1α, skeletal muscle metabolism shifts toward oxidative pathways at ZT3, with notable alterations in glucose fate. These results establish HIF1α as an important regulator of time-of-day-specific metabolic adaptations, integrating circadian and energetic signals to optimize substrate utilization. This work highlights the broader significance of HIF1α in coordinating circadian influences on metabolic health and exercise performance.

Keywords:  circadian; energy metabolism; exercise; metabolism; transcription factor

DOI:  https://doi.org/10.1073/pnas.2504080122
Adv Sci (Weinh). 2025 Jul 11. e02402

Abnormal β-Hydroxybutyrylation Modification of ARG1 Drives Reprogramming of Arginine Metabolism to Promote the Progression of Colorectal Cancer.

Chuman Lin, Zhiyang Li, Xiaotong Zhu, Wanbing Zhou, Xiansheng Lu, Jiali Zheng, Jie Lin.

  The abnormal arginine metabolism is characteristic of tumor cell metabolism in colorectal cancer (CRC). However, the mechanisms underlying arginine metabolic reprogramming and how altered metabolism in turn enhances CRC tumorigenicity are poorly understood. Protein post-translational modifications (PTMs) are crucial for regulating protein function, activity, and interactions. Here, the study reports that arginine levels are elevated in CRC, accompanied by the high expression of arginase-1 (ARG1) but low levels of ARG1 β-hydroxybutyrylation (Kbhb) and its oncogenic role in CRC in a catalytic-activity-independent manner. Mechanistically, low-level ARG1-Kbhb-induced arginine metabolic reprogramming by decreasing the interaction of ARG1 with SLC3A2 in CRC cells inhibits the efflux of arginine, thereby increasing intracellular arginine levels to promote tumorigenicity. P300 is identified as the "writer" of Kbhb. Inducing ARG1-Kbhb at the Lys313 residue by β-hydroxybutyrate (BHB) promotes the interaction of ARG1 with SLC3A2, resulting in the efflux of arginine in CRC cells. Together, these findings reveal valuable insights into arginine metabolism reprogramming involving the ARG1-Kbhb/P300/SLC3A2 signaling axis, thereby bridging the connection between metabolic reprogramming and PTMs, which may shed light on the therapeutic potential of combining BHB with ARG1 inhibitor through the conventional enzymatic role and nonenzymatic metabolic function of ARG1 for CRC.

Keywords:  ARG1; arginine metabolism reprogramming; colorectal cancer; β‐hydroxybutyrylation

DOI:  https://doi.org/10.1002/advs.202502402
Cancer Metab. 2025 Jul 10. 13(1): 35

Fatty acid synthase-derived lipid stores support breast cancer metastasis.

Chaylen Andolino, Eylem Kulkoyluoglu Cotul, Zilin Xianyu, Yun Li, Divya Bhat, Mitchell Ayers, Kimberly K Buhman, Stephen D Hursting, Michael K Wendt, Dorothy Teegarden.

  Lipid accumulation is associated with breast cancer metastasis. However, the mechanisms underlying how breast cancer cells increase lipid stores and their functional role in disease progression remain incompletely understood. Herein we quantified changes in lipid metabolism and characterized cytoplasmic lipid droplets in metastatic versus non-metastatic breast cancer cells. 14C-labeled palmitate was used to determine differences in fatty acid (FA) uptake and oxidation. Despite similar levels of palmitate uptake, metastatic cells increase lipid accumulation and oxidation of endogenous FAs compared to non-metastatic cells. Isotope tracing also demonstrated that metastatic cells support increased de novo lipogenesis by converting higher levels of glutamine and glucose into the FA precursor, citrate. Consistent with this, metastatic cells displayed increased levels of fatty acid synthase (FASN) and de novo lipogenesis. Genetic depletion or pharmacologic inhibition of FASN reduced cell migration, survival in anoikis assays, and in vivo metastasis. Finally, global proteomic analysis indicated that proteins involved in proteasome function, mitotic cell cycle, and intracellular protein transport were reduced following FASN inhibition of metastatic cells. Overall, these studies demonstrate that breast cancer metastases accumulate FAs by increasingde novo lipogenesis, storing TAG as cytoplasmic lipid droplets, and catabolizing these stores to drive several FAO-dependent steps in metastasis.

Keywords:  Breast cancer; FASN; Fatty acid synthase; Fatty acids; Lipid droplet; Lipid metabolism; Lipid storage; Mass spectrometry; Metastasis; TNBC

DOI:  https://doi.org/10.1186/s40170-025-00404-3
Cancer Biol Ther. 2025 Dec;26(1): 2529652

USP44 promotes chemotherapeutic drug resistance of triple negative breast cancer through EZH2 protein stability.

Pu Wu, Wanting Xiao, Junjie Ni, Yuming Lou, Chaoyang Xu.

  Triple negative breast cancer (TNBC), a highly invasive breast cancer, is one of the leading causes of cancer-related mortality worldwide. Although chemotherapy remains the standard of care for TNBC, the development of chemotherapy resistance significantly limits its clinical efficacy. In this study, we identified the deubiquitinating enzyme USP44 as a contributor to chemoresistance in TNBC and investigated the potential regulatory feedback mechanisms involved. In this experimental study, we investigated the sensitivity of TNBC cells MDA-MB-231 and BT-549 to chemotherapy drugs after overexpression and knockdown of USP44 using CCK-8 reagent kit and flow cytometry analysis, respectively. Western blot was performed to evaluate the expression levels of relevant proteins. In vivo xenograft models were established to examine the effects of USP44 and its downstream targets on chemosensitivity. Co-immunoprecipitation assay and ubiquitination assay were conducted to identify interacting proteins and elucidate the underlying molecular mechanisms. Knockdown of USP44 increased the sensitivity of MDA-MB-231 and BT-549 cells to chemotherapeutic agents, accompanied by elevated levels of Cleaved PARP. In contrast, USP44 overexpression reduced drug sensitivity. Mechanistically, USP44 was found to interact with EZH2, preventing its ubiquitination and subsequent proteasomal degradation. Notably, treatment with GSK126, a specific EZH2 inhibitor, reversed the chemoresistance induced by USP44 overexpression. USP44/EZH2 signaling pathway is one of the key to causing the drug resistance of TNBC, warranting further clinical investigation.

Keywords:  EZH2; Triple-negative breast cancer; USP44; drug resistance

DOI:  https://doi.org/10.1080/15384047.2025.2529652
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2413732122

DNA2 protein destruction dictates DNA hyperexcision, cGAS-STING activation, and innate immune response in CDK12-deregulated cancers.

Rui Sun, Peng Jiang, Zhijun Wang, Binyuan Yan, Shouhai Zhu, Zhenlin Huang, Jianong Zhang, Donglin Ding, Xiang Li, Liguo Wang, Zhenkun Lou, Baiye Jin, Jun Pang, Haojie Huang, Dan Xia.

  CDK12 primarily functions as a transcription regulatory cyclin-dependent kinase (CDK) that controls mRNA elongation, splicing, and polyadenylation. The CDK12 gene is implicated in human cancers since it is frequently mutated and/or deleted in prostate and ovarian cancer but paradoxically amplified in breast cancer. Here, we demonstrate that CDK12 promotes serine-933 phosphorylation of DNA2, a nuclease/helicase critical for replication fork stress regulation, and the phosphorylation subsequently facilitates DNA2 polyubiquitination and degradation mediated by the APC/CCDC20 E3 ubiquitin ligase. CDK12 inactivation induces but amplification suppresses genome-wide expression of interferon response and antigen processing and presentation machinery genes in ovarian and breast cancer cells, respectively. Besides causing aberrant DNA2 stabilization, replication stress, genomic instability, and cytosolic double-stranded DNA (dsDNA) accumulation, CDK12 loss also triggers cGAS-STING activation and innate immune response, which can be reversed by forced expression of replication protein A (RPA) subunits or DNA2 depletion. Our findings identify DNA2 as a phosphorylation substrate of CDK12, connecting CDK12 to cell cycle regulation. These data also reveal DNA2 protein destruction as a critical mechanism that dictates genomic instability, cGAS-STING signaling activation, and innate immune response in CDK12-deregulated cancers.

Keywords:  DNA resection; cGAS-STING; innate immunity; prostate cancer; ubiquitination

DOI:  https://doi.org/10.1073/pnas.2413732122
Expert Opin Ther Targets. 2025 Jul 11.

Metabolic hallmarks of trastuzumab resistance.

Begoña Martin-Castillo, Sara Verdura, Àngela Llop-Hernández, Ruth Lupu, Elisabet Cuyàs, Javier A Menendez.

   INTRODUCTION: The HER2-targeted monoclonal antibody trastuzumab has significantly improved the survival of patients with HER2-positive breast cancer (HER2+ BC) in both early and metastatic disease. Therapeutic resistance remains an inevitable challenge in the advanced setting, ultimately limiting the long-term efficacy of trastuzumab. Numerous mechanisms of trastuzumab resistance and response heterogeneity have been described, most involving alterations in HER2 receptor levels and reactivation of HER2 downstream signaling. However, the growing number of metabolic escape routes that allow HER2+ BC cells to evade HER2 inhibition have received little attention.
AREAS COVERED: We comprehensively review the metabolic strategies that HER2+ BC cells adopt to enable trastuzumab resistance, grouping them into a structured classification that takes into account their functional nature, namely: (1) metabolic reprogramming - how cells maintain an adequate supply of energy and biosynthetic precursors to survive, grow and proliferate despite HER2 inhibition; (2) adaptive stress response - how cells increase their resilience to survive trastuzumab-induced stress and damage; and (3) metabolic-signaling crosstalk - how key survival pathways redirect metabolism to reinforce trastuzumab resistance feedback loops.
EXPERT OPINION: The metabolic hallmarks of trastuzumab resistance may help to identify high-quality predictive biomarkers and to rationally develop optimized therapeutic strategies to counteract trastuzumab resistance metabolically.

Keywords:  HER2 therapies; autophagy; bioenergetics; metabolism; therapy resistance

DOI:  https://doi.org/10.1080/14728222.2025.2532394
Bioact Mater. 2025 Oct;52 702-718

Antibody-functionalized iron-based nanoplatform for ferroptosis-augmented targeted therapy of HER2-positive breast cancer.

Jingchao Gao, Tong Ye, Hongkun Miao, Mingjiang Liu, Li Wen, Yi Tian, Zhiguang Fu, Li Sun, Lihong Wang, Yu Wang.

  Human epidermal growth factor receptor 2 positive (HER2+) breast cancer, as a subtype with high invasiveness and poor prognosis, faces issues of intertumoral heterogeneity and signaling pathway dysregulation leading to trastuzumab resistance in clinical treatment. Therefore, innovative therapeutic strategies are urgently needed to enhance treatment efficacy and improve patient prognosis. In this study, we proposed an antibody-targeted nanoplatform responsive to the tumor microenvironment, aiming to induce ferroptosis in HER2+ breast cancer cells and thereby enhance the sensitivity to HER2-targeted drugs. Fe-MOF@Erastin@Herceptin (FEH) was prepared by loading Erastin onto mesoporous Fe-MOF and modifying it with trastuzumab (a HER2+ breast cancer cell-specific antibody). This platform gradually releases trastuzumab, Erastin, and Fe3+ in the tumor microenvironment. The modification of trastuzumab enhances tumor cell targeting while reducing toxicity to non-target cells and tissues. Erastin inhibits system XC - to reduce glutathione (GSH) synthesis. Fe3+ consumes glutathione and reduces itself to Fe2+ via a reduction reaction, which further enhances the catalytic effect of H2O2 and triggers the Fenton reaction to generate large amounts of reactive oxygen species (ROS). In the antibody-targeted cascade reaction, decreased intracellular GSH content and increased Fe2+ and ROS can further promote lipid peroxidation and down-regulation of glutathione peroxidase 4 (GPX4) in breast cancer cells, inducing ferroptosis. The experimental results indicate that FEH can significantly improve the tumor microenvironment by enhancing ferroptosis effects, providing a potential new strategy for precision therapy of HER2+ breast cancer cells.

Keywords:  Ferroptosis; GPX4; HER2-positive breast cancer; Nano-materials; SLC7A11

DOI:  https://doi.org/10.1016/j.bioactmat.2025.06.034
Cell Immunol. 2025 Jun 28. pii: S0008-8749(25)00086-3. [Epub ahead of print]414 105000

Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.

Annefien Tiggeler, Paul J Coffer.

  Upon activation, naïve T cells undergo rapid proliferation and differentiation, giving rise to clonally expanded populations specifically tailored for an effective immune response. To meet the heightened bioenergetic and biosynthetic demands associated with activation, T cells adapt and reprogram both their metabolism and transcriptome. Beyond this, T cells are also able to dynamically adapt to fluctuations in the microenvironmental nutrient levels. While the adaptability of T cells is a well-established hallmark of their functionality, the molecular mechanisms by which metabolic responses underpin this flexibility remain incompletely defined. Acetyl-CoA, with its role as a central metabolite in mitochondrial ATP production, and a substrate for nuclear histone acetylation reactions, emerges as a key player in a metabolic-epigenetic axis. Recent evidence indicates that enzymes responsible for generating acetyl-CoA can translocate to the nucleus, supporting sub-cellular local acetyl-CoA production. Here, we explore the impact of acetyl-CoA metabolism on T cell functionality within different subcellular compartments and highlight the potential for intervention in acetyl-CoA metabolic pathways in T cell-driven autoimmune diseases and cancers.

Keywords:  Acetyl-CoA; Epigenetic remodelling; Metabolic reprogramming; Nuclear metabolism; T cells

DOI:  https://doi.org/10.1016/j.cellimm.2025.105000
J Proteome Res. 2025 Jul 07.

Identifying Links between Alzheimer's Disease and Type 2 Diabetes through Proteomics.

Tong N Chen, Adam L Orr, Anna G Orr, Nathaniel M Vacanti.

  Alzheimer's disease (AD) and type 2 diabetes (T2D) are both amyloidogenic, age-associated chronic diseases and their occurrences are linked by epidemiological evidence and common dysregulated molecular functions including glucose hypometabolism, dyslipidemias, and altered insulin signaling. High-throughput molecular profiling of the genome and transcriptome has advanced our understanding of their molecular links; however, proteomic signatures may reveal novel biomarkers and additional insights because proteins are the primary purveyors of molecular function. Herein, the contributions to our understanding of the molecular links between AD and T2D by high-throughput proteomics are reviewed. Collectively, the studies highlight strong, but broad, common molecular and metabolic signatures; however, more investigation is needed to define shared mechanisms and identify robust biomarkers and potential therapeutic targets.

Keywords:  Alzheimer’s; diabetes; high-throughput; insulin; interaction; metabolism; molecular; profiling; proteome; resistance

DOI:  https://doi.org/10.1021/acs.jproteome.5c00404