bims-cesirm 2026-02-01 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2026–02–01
23 papers selected by
Tigist Tamir, University of North Carolina

Chemical Proteomics Reveals Regulation of Bile Salt Hydrolases via Oxidative Post-translational Modifications.
Multiplexed Quantitation of Post-Translationally Modified Peptides in Single Cells Using Triggered MS/MS Combined with Super Heavy Tandem Mass Tags.
A Thermodynamic Constraint on GPx4 Flux Links Glutathione Redox State to Ferroptotic Commitment.
OGDHL promotes prostate cancer progression and regulates neuroendocrine marker expression and nucleotide abundance.
Proteomic Profiling of Oxidative Stress Response Proteins with a Methionine Sulfoxide-Inspired Activity-Based Probe.
A novel extracellular vesicle-engineered immunotherapy drug for Her2+ breast cancer.
Coordination of cell organelles to promote metabolon formation.
Nicotinamide N-Methyl Transferase (NNMT) Sustains Innate Sensitivity to NAMPT Inhibition in YAP-dependent Stem-like/Mesenchymal Prostate Cancer.
Epigenetic alterations of AKT1 orchestrate a metabolic reprogramming in advanced lipedema: translational insights from an integrated multi-omics study.
Machine learning for enzyme catalytic activity: current progress and future horizons.
GLP-1 RA initiation versus metformin and risk of cardiomyopathy in patients with cancer and diabetes treated with chemotherapy, radiation, or immunotherapy: a target trial emulation.
Non-Canonical Senescence Phenotype in Resistance to CDK4/6 Inhibitors in ER-Positive Breast Cancer.
HMGCS2 desuccinylation modulates acetoacetate to drive tubule-macrophage inflammatory crosstalk in diabetic kidney disease.
Breast Cancer Metastases Harbor Tissue-Specific Metabolic Dependencies.
The Dual Anaplerotic Model (DAM): Integral Roles of Pyruvate Carboxylase and the GABA Shunt in Beta Cell Insulin Secretion.
Metabolomic Signatures of Recovery: A Secondary Analysis of Public Longitudinal LC-MS Datasets Shows Polyphenol-Rich Interventions Attenuate Purine Degradation and Oxidative Stress Following Exhaustive Exercise.
The combination of rosuvastatin and meloxicam enhances the radiotherapy efficacy of MCF7, T-47D, and MDA-MB-231 breast cancer cell lines.
Metabolic Signatures of Breast Cancer Subtypes and the Metabolic Impact of Chemotherapy.
Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial.
A metabolic basis for motor deficits in mice lacking BCKDK.
Mitochondrial Redox Vulnerabilities in Triple-Negative Breast Cancer: Integrative Perspectives and Emerging Therapeutic Strategies.
Metabolic Landscape of Endometrial Cancer: Insights into Pathway Dysregulation and Metabolic Features.
Subcellular mass spectrometry reveals proteome remodeling in an asymmetrically dividing (frog) embryonic stem cell.

J Am Chem Soc. 2026 Jan 29.

Chemical Proteomics Reveals Regulation of Bile Salt Hydrolases via Oxidative Post-translational Modifications.

Amy K Bracken, Kien P Malarney, Pamela V Chang.

The gut microbiome is the vast, diverse ecosystem of microorganisms that inhabits the human intestines and provides numerous essential functions for the host. One such key role is the metabolism of primary bile acids that are biosynthesized in the host liver into a plethora of secondary bile acids produced by gut bacteria. These metabolites serve as both antimicrobial and chemical signaling agents within the host. The critical microbial enzyme that plays a gatekeeping role in secondary bile acid metabolism is bile salt hydrolase (BSH), a cysteine hydrolase that is primarily known for its deconjugating and reconjugating activities on bile acid substrates. Despite the crucial nature of these biotransformations, regulation of BSH activity is not well understood. Here, we found that the catalytic cysteine 2 (Cys2) within the BSH active site exists in multiple sulfur oxidation states including sulfenic acid (Cys-SOH). Importantly, we show this reversible oxidative post-translational modification (oxPTM) ablates BSH catalytic activity. We have leveraged this discovery to develop a chemoproteomic platform featuring a sulfenic acid-reactive bile acid probe to profile BSH Cys2 oxPTMs throughout the gut microbiome. Our results reveal that though most gut microbiota-associated BSHs exist in the active Cys2-SH state, some are preferentially and reversibly inactivated in the Cys2-SOH state. This reversible oxidation of Cys2 may serve as a general mechanism to regulate BSH activity in vivo in response to a changing physiological environment.

DOI: https://doi.org/10.1021/jacs.5c18912
J Proteome Res. 2026 Jan 27.

Multiplexed Quantitation of Post-Translationally Modified Peptides in Single Cells Using Triggered MS/MS Combined with Super Heavy Tandem Mass Tags.

Dong-Gi Mun, Hiroshi Nishida, Firdous A Bhat, Raghavendra Rao Pasupuleti, Bernard Delanghe, Akhilesh Pandey.

  Recent advances in mass spectrometry permit unbiased proteome profiling of thousands of proteins from single cells using both label-free and labeling approaches. However, a major limitation of unbiased approaches is missing data, which worsens as the sample size increases. In addition, the reproducible measurement of post-translational modifications (PTMs) at the single cell level, particularly those present at a lower stoichiometry than their unmodified counterparts, poses an even greater challenge. To overcome this limitation, we developed a targeted strategy that combines tandem mass tag (TMT) multiplexing with SureQuant-based triggered MS/MS using super heavy TMT-labeled peptides that are 9 Da heavier than the TMTpro tags as triggers. To demonstrate the feasibility of our approach, we established a method quantifying four PTMs on the histone H3 protein (i.e., K14ac, K23ac, K27me, K27me3, and K79me) at single-cell resolution. We demonstrated robustness in quantitation compared to conventional approaches of data-dependent acquisition and standard parallel reaction monitoring. Further, we applied this strategy to single cells and revealed cellular heterogeneity in histone PTMs. Overall, we developed a targeted strategy with improved sensitivity and throughput for analyzing PTMs in single cells, which we expect will be broadly applicable to multiple types of PTMs while enabling focused analysis.

Keywords:  PTM; SureQuant; single cell proteomics; super heavy tandem mass tags

DOI:  https://doi.org/10.1021/acs.jproteome.5c00972
Free Radic Biol Med. 2026 Jan 23. pii: S0891-5849(26)00057-2. [Epub ahead of print]

A Thermodynamic Constraint on GPx4 Flux Links Glutathione Redox State to Ferroptotic Commitment.

Fulvio Ursini, Antonella Roveri, Matilde Maiorino, Laura Orian.

  Ferroptosis is a non-accidental form of cell death driven by lipid peroxidation and critically controlled by the selenoenzyme Glutathione Peroxidase 4 (GPx4). By integrating molecular modeling, redox thermodynamics, and enzymatic evidence, we propose that ferroptosis is governed by the redox potential of the glutathione couple, elevating current mechanistic descriptions to a quantitative physical-chemical framework. The terminal step of the GPx4 catalytic cycle-responsible for enzyme regeneration and oxidized glutathione (GSSG) formation-is intrinsically endergonic, and its driving force declines continuously as the glutathione redox potential becomes less reducing. As a result, GPx4 activity decreases linearly in accordance with Nernstian principle, independently of discrete inhibitory events. Within this framework, ferroptosis is not initiated by a discrete molecular trigger or canonical signaling cascade; rather, it emerges when a critical biological threshold is surpassed, such that GPx4-dependent detoxification capacity is no longer sufficient to counteract ongoing lipid peroxidation within a given pro-oxidant context. Thus, a discrete cell-death outcome executed by GSSG emerges from the continuous variation of a thermodynamic control variable. This mode of regulation is unique to selenium chemistry and provides a physical-chemical rationale for the indispensability of selenocysteine in the redox control of cellular life and death.

Keywords:  Ferroptosis; GPx4; Glutathione peroxidases; Glutathione redox potential; Lipid peroxidation; Redox homeostasis; Redox thermodynamics; Selenocysteine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.039
Mol Cancer Res. 2026 Jan 27.

OGDHL promotes prostate cancer progression and regulates neuroendocrine marker expression and nucleotide abundance.

Matthew J Bernard, Andrea Gallardo, Angel Ruiz, Johnny A Diaz, Nicholas M Nunley, Rachel N Dove, Shile Zhang, Ernie Lee, Kylie Y Heering, Grigor Varuzhanyan, Sachi Bopardikar, Takao Hashimoto, Raag Agrawal, Chad M Smith, Blake R Wilde, Nedas Matulionis, Helen M Richards, Sandy Che-Eun S Lee, Marina N Sharifi, Joshua M Lang, Shuang G Zhao, Owen N Witte, Michael C Haffner, David B Shackelford, Paul C Boutros, Heather R Christofk, Andrew S Goldstein.

As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL reduces nucleotide synthesis, induces accumulation of the DNA damage response marker ƔH2AX, and alters Androgen Receptor inhibition-induced plasticity. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer, and that knockdown of OGDHL impairs growth of cell line models of neuroendocrine prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer. Implications: OGDHL emerged as an unexpected metabolic dependency associated with lineage plasticity and neuroendocrine differentiation, implicating poorly studied metabolic enzymes as potential targets for treatment-resistant prostate cancer.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0913
JACS Au. 2026 Jan 26. 6(1): 310-318

Proteomic Profiling of Oxidative Stress Response Proteins with a Methionine Sulfoxide-Inspired Activity-Based Probe.

Seungmin Ahn, Jung-Min Kee.

  Methionine oxidation is a key hallmark of cellular oxidative stress, which is reversed by methionine sulfoxide reductases (Msrs) as part of cellular defense mechanisms. Current tools for studying methionine oxidation and Msr function rely on sulfoxide reduction or transcriptional analysis, which are inadequate for monitoring enzyme activity under persistent oxidative stress. Moreover, no activity-based protein profiling (ABPP) tools have been reported for investigating the functional state of Msrs in cells. Here, we present SO-acetylene, a methionine sulfoxide-inspired, cysteine-reactive probe for profiling Msrs and other proteins involved in oxidative stress responses. This substrate-inspired probe preferentially labels catalytic cysteines of Msrs, serving as an activity-based probe. The application of SO-acetylene to Escherichia coli under hypochlorite stress resulted in the labeling of multiple oxidative stress-related proteins, revealing distinct activity patterns among Msrs that diverge from transcriptional regulation. Furthermore, comparative labeling experiments with the conventional probe iodoacetamide revealed that SO-acetylene provides complementary coverage of cysteine reactivity, efficiently capturing the active-site cysteine of a DJ-1 superfamily glyoxalase, which is poorly labeled by iodoacetamide-alkyne.

Keywords:  activity-based protein profiling; chemoproteomics; cysteine reactivity; hypochlorite stress; methionine sulfoxide reductase; oxidative stress

DOI:  https://doi.org/10.1021/jacsau.5c01237
J Adv Res. 2026 Jan 25. pii: S2090-1232(26)00092-5. [Epub ahead of print]

A novel extracellular vesicle-engineered immunotherapy drug for Her2+ breast cancer.

Xinliang Lu, Weiyi Yuan, Xianchang Zeng, Fanghui Zhang, Chengyan Zhang, Xinrong Li, Jufeng Guo, Jiayue Hao, Gensheng Zhang, Jianli Wang, Hao Wu, Zhijian Cai.

  Trastuzumab profoundly improves outcomes of Her2+ breast cancer (BC) patients, but eventual drug resistance is inevitable. Therefore, new treatment options are urgently needed. Here, we modify extracellular vesicles (EVs) with a Her2 single-chain variable fragment of trastuzumab (EVs/Her2-scFv) to target Her2+ BC and found that EVs/Her2-scFv inhibit human Her2+ orthotopic BC comparable to trastuzumab and also uniquely suppress brain metastasies. Moreover, EVs/Her2-scFv loaded with rabeprazole (EVs/Her2-scFv/Rabe) effectively improve tumor immunosuppressive microenvironment and abnormal vasculature of Her2+ BC by reducing tumor EVs. When further anchored with CD8+ T cell chemotactic CXCL9, CXCL9-loaded EVs/Her2-scFv/Rabe (EVs/Her2-scFv/CXCL9/Rabe) facilitate CD8+ T cell recruitment and subsequent activation, thereby exhibiting immunotherapeutic effects on mouse Her2+ BC. In BC patient-derived tumor organoids (PDOs) and peripheral blood mononuclear cell coculture systems, EVs/Her2-scFv/CXCL9/Rabe limit PDO growth by blocking Her2 signaling and activating CD8+ T cells. Besides, EVs/Her2-scFv/CXCL9/Rabe are low-immunogenic with biosafety. Altogether, EVs/Her2-scFv/CXCL9/Rabe hold high potential in Her2+ BC therapy.

Keywords:  Brain metastatic tumors; CXCL9; Extracellular vesicles; Her2; Rabeprazole

DOI:  https://doi.org/10.1016/j.jare.2026.01.067
Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2532504123

Coordination of cell organelles to promote metabolon formation.

Zhou Sha, Anthony M Pedley, Timothy D Iles, Shaoqing Zhang, Jack R Staub, Ruobo Zhou, Stephen J Benkovic.

  The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5'-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.

Keywords:  biomolecular condensates; cell metabolism; de novo purine biosynthesis; metabolon; purine

DOI:  https://doi.org/10.1073/pnas.2532504123
Int J Biol Sci. 2026 ;22(3): 1126-1141

Nicotinamide N-Methyl Transferase (NNMT) Sustains Innate Sensitivity to NAMPT Inhibition in YAP-dependent Stem-like/Mesenchymal Prostate Cancer.

Ágata Sofia Assunção Carreira, Marianna Ciuffreda, Nathakan Thongon, Charles M Haughey, Adam Pickard, Sharon L Eddie, Rebecca E Steele, Elena Cerri, Romina Belli, Daniele Peroni, Elisa Facen, Irene Caffa, Moustafa Ghanem, Alessio Nencioni, Andrea Lunardi, Toma Tebaldi, Ian G Mills, Alessandro Provenzani.

  Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway and a promising therapeutic target in cancer. Resistance to NAMPT inhibitors, such as FK866, remains a key limitation to their clinical translation. While acquired resistance in cancer cell lines has been linked to target mutations, increased drug efflux, and metabolic reprogramming, innate resistance mechanisms have been poorly studied. Addressing this gap is crucial for identifying patient subgroups that are most likely to benefit from NAMPT-targeted therapies. Advanced castration resistance prostate cancer (CRPC) lacks effective targeted treatments. Among its heterogeneous subtypes, stem cell-like CRPC (CRPC-SCL) is characterized by independence from androgen receptor (AR) signaling, dependency on YAP/TAZ, and mesenchymal traits. In this study, we identify the YAP/nicotinamide N-methyltransferase (NNMT) axis as a key regulator of innate sensitivity to FK866 in stem-like mesenchymal CRPC cells. Using genetic and pharmacological models, we show that YAP or NNMT silencing rescues PC3 cells from FK866-induced apoptosis, endoplasmic reticulum stress, and NAD(H) depletion. Metabolomic profiling confirmed that NNMT activity depletes nicotinamide, sensitizing cells to FK866. We further validated NNMT upregulation across clinical CRPC-SCL datasets, where it strongly correlates with mesenchymal and therapy-resistant phenotypes. Murine prostate cancer cells with mesenchymal/stemness phenotypes (DVL3-SCM), that exhibit NNMT overexpression and high aggressiveness in vivo, also show increased sensitivity to FK866 compared with their parental counterparts (DVL3-PAR). In conclusion, we identify the YAP/NNMT axis as a determinant of innate sensitivity to NAMPT inhibition in prostate cancer. These findings support the use of NNMT as a predictive biomarker for NAD+-targeting therapies and provide mechanistic insight into a metabolic vulnerability of the CRPC-SCL subtype. Targeting the YAP/NNMT/NAMPT axis may represent a novel strategy for treating stem-like/mesenchymal, therapy-resistant prostate cancers.

Keywords:  CRPC; EMT; FK866; NAMPT; NNMT; Stemness; YAP

DOI:  https://doi.org/10.7150/ijbs.120532
J Transl Med. 2026 Jan 24.

Epigenetic alterations of AKT1 orchestrate a metabolic reprogramming in advanced lipedema: translational insights from an integrated multi-omics study.

Biagio Santella, Annamaria Salvati, Alexander Papp, Annamaria D'Ursi, Domenico Memoli, Monica Mingo, Christoph Pulai, Carmen Marino, Luca Rastrelli, Maria D'Elia, Giovanni Nassa, Luigi Schiavo.

   BACKGROUND: lipedema is a chronic, progressive adipose disorder predominantly affecting women, characterized by painful, symmetrical subcutaneous fat accumulation, and typically resistant to lifestyle interventions. The pathophysiology of advanced-stage lipedema remains poorly defined, and no validated biomarkers or targeted therapies are currently available.
METHODS: in this observational study, we applied a comprehensive multi-omics approach to dissect the molecular and metabolic alterations underlying late-stage lipedema.
RESULTS: Genome-wide DNA methylation profiling identified over 5,000 differentially methylated CpG sites affecting genes involved in receptor tyrosine kinase signaling, phospho-metabolism, and immune pathways. Transcriptomic analysis revealed profound downregulation of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and fatty acid β-oxidation, alongside disruption of the sirtuin pathway and extracellular matrix remodeling. Integrative analysis pinpointed AKT1 as a central regulatory node: its promoter region was hypomethylated, correlating with increased gene expression and protein phosphorylation. Metabolomic profiling confirmed AKT1-linked metabolic dysregulation, including altered levels of L-arginine, NADP+, ATP, guanosine, glycerol, and glutamate, indicating impaired redox balance and energy metabolism. Trans-omic network analysis positioned AKT1 at the intersection of multiple dysregulated pathways, suggesting its key role in advanced-stage lipedema.
CONCLUSIONS: the consistent enhancing of AKT pathway signaling across omic layers highlights its potential not only as a biomarker for disease stratification but also as a putative druggable target for therapeutic intervention. These findings offer new mechanistic insights into lipedema pathophysiology and provide a rationale for future personalized treatment strategies guided by AKT1-centric molecular profiling.

Keywords:  AKT1 signaling; DNA methylation; Epigenetic regulation; Lipedema; Mitochondrial dysfunction; Multi-omics integration

DOI:  https://doi.org/10.1186/s12967-026-07726-w
Brief Bioinform. 2026 Jan 07. pii: bbag002. [Epub ahead of print]27(1):

Machine learning for enzyme catalytic activity: current progress and future horizons.

Sizhe Qiu, Haris Saeed, Will Leonard, Feiran Li, Aidong Yang.

  Enzyme catalysis, with its advantages in environmental sustainability and efficiency, is gaining traction across diverse industrial applications, such as waste utilization and pharmaceutical biomanufacturing. However, optimizing enzyme catalytic activity remains a significant challenge. To facilitate enzyme mining and engineering, machine learning (ML) models have emerged to predict enzyme substrate specificity, enzyme turnover number, and enzyme catalytic optimum. This review endeavored to assist researchers in effectively utilizing predictive models for enzyme catalytic activity through presenting recent advancements and analyzing different approaches. We also pointed out existing limitations (e.g. dataset imbalance) and offered suggestions on potential enhancements to address them. We identified that the attention mechanism, inclusion of new features such as product information and temperature, and using transfer learning to leverage different datasets were three main useful modeling strategies. Furthermore, we envisaged that accurate predictors of enzyme catalytic activity would potentially transform enzyme and metabolic engineering, and the optimization of biocatalysis.

Keywords:  compound-protein interaction; deep learning; enzyme catalytic optimum; enzyme substrate specificity; enzyme turnover number

DOI:  https://doi.org/10.1093/bib/bbag002
Diabetes Res Clin Pract. 2026 Jan 26. pii: S0168-8227(26)00038-0. [Epub ahead of print] 113119

GLP-1 RA initiation versus metformin and risk of cardiomyopathy in patients with cancer and diabetes treated with chemotherapy, radiation, or immunotherapy: a target trial emulation.

Jesús Gibran Hernández-Pérez, Omer Abdelgadir, Maryam R Hussain, Jaime P Almandoz, Carlos H Barcenas, Amil Shah, Lindsay G Cowell, Sarah E Messiah, David S Lopez.

   AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have demonstrated cardioprotective effects; however, their association with cardiomyopathy remains unclear among patients with cancer and type 2 diabetes mellitus (T2D) treated with chemotherapy, radiation, or immunotherapy. We evaluated whether GLP-1 RA initiation reduces cardiomyopathy risk compared with metformin.
METHODS: We conducted a retrospective cohort study using a target trial emulation framework within a large global electronic health record database. Adults aged 18-75 years with cancer and T2D, and prior exposure to chemotherapy, radiation, or immunotherapy were included. Treatment strategies were initiation of GLP-1 RA or metformin between January 2006 and July 2024. The primary outcome was incident cardiomyopathy. A 1:1 propensity score-matched cohort was created, and risk differences (RD) and hazard ratios (HR) were estimated.
RESULTS: Among 10,382 matched patients, cardiomyopathy risk at 18.5 years was lower among GLP-1 RA initiators than metformin initiators (0.31% vs 0.94%; RD - 0.64%, 95% CI - 0.90 to - 0.30; HR 0.43, 95% CI 0.24-0.76). Results were consistent across high-risk subgroups.
CONCLUSIONS: GLP-1 RA initiation was associated with a lower risk of cardiomyopathy compared with metformin among patients with cancer and T2D, supporting a potential role for GLP-1 RA in cardio-oncology prevention strategies.

Keywords:  Cancer; Cardio-oncology; Cardiomyopathy; Glucagon-like peptide-1 receptor agonists; Metformin; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.diabres.2026.113119
Biomolecules. 2026 Jan 06. pii: 93. [Epub ahead of print]16(1):

Non-Canonical Senescence Phenotype in Resistance to CDK4/6 Inhibitors in ER-Positive Breast Cancer.

Aynura Mammadova, Yuan Gu, Ling Ruan, Sunil S Badve, Yesim Gökmen-Polar.

  Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for estrogen receptor-positive (ER+) breast cancer, yet resistance remains a major clinical challenge. Although CDK4/6i induce G1 arrest and therapy-induced senescence (TIS), the exact nature of this senescent state and its contribution to resistance are not well understood. To explore this, we developed palbociclib- (2PR, 9PR, TPR) and abemaciclib- (2AR, 9AR, TAR) resistant ER+ breast cancer sublines through prolonged drug exposure over six months. Resistant cells demonstrated distinct phenotypic alterations, including cellular senescence, reduced mitochondrial membrane potential, and impaired glycolytic activity. Cytokine profiling and enzyme-linked immunosorbent assay (ELISA) validation revealed a non-canonical senescence-associated secretory phenotype (SASP) characterized by elevated growth/differentiation factor 15 (GDF-15) and serpin E1 (plasminogen activator inhibitor-1, PAI-1) and absence of classical pro-inflammatory interleukins, including IL-1α and IL-6. IL-8 levels were significantly elevated, but no association with epithelial-mesenchymal transition (EMT) was observed. Resistant cells preserved their epithelial morphology, showed no upregulation of EMT markers, and lacked aldehyde dehydrogenase 1-positive (ALDH1+) stem-like populations. Additionally, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) was strongly upregulated in palbociclib-resistant cells. Together, these findings identify a distinct, non-canonical senescence phenotype associated with CDK4/6i resistance and may provide a foundation for identifying new vulnerabilities in resistant ER+ breast cancers through targeting SASP-related signaling.

Keywords:  CDK4/6 inhibitors; breast cancer; resistance to cancer therapies; therapy-induced senescence

DOI:  https://doi.org/10.3390/biom16010093
Metabolism. 2026 Jan 22. pii: S0026-0495(26)00019-3. [Epub ahead of print]177 156510

HMGCS2 desuccinylation modulates acetoacetate to drive tubule-macrophage inflammatory crosstalk in diabetic kidney disease.

Ziyue Lin, Dan Lv, He Zha, Handeng Liu, Rui Peng, Jiakun Yang, Wuchao Li, Xiaohui Liao, Yan Sun, Zheng Zhang.

  Mitochondrial dysfunction in renal tubular epithelial cells (TECs) is a hallmark of diabetic kidney disease (DKD), accompanied by macrophage infiltration, yet how metabolic perturbations in TECs-macrophage driven inflammation remains unclear. Here, we identify 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, as a critical mediator linking tubular mitochondrial stress to macrophage M1 polarization in DKD. In mice subjected to DKD, conditional knockout HMGCS2 in TECs decreases mitochondrial fission of TECs, M1 macrophage infiltration and tubular inflammatory injury. Combining LC-MS/MS and ketone flux detection reveals that desuccinylated HMGCS2 produced more acetoacetate (AcAc) than beta-hydroxybutyrate (β-HB) in TECs of DKD. Mechanistically, Signal Transducer and Activator of Transcription 3 (STAT3) promotes Hmgcs2 transcription and sirtuin 5 (SIRT5) activates HMGCS2 through lysine desuccinylation at K367, which promotes AcAc overload shuttling from TECs to macrophages. AcAc acts as a signaling metabolite to activate the MIF/ERK pathway, driving M1 polarization and amplifying a pro-inflammatory feedback loop of tubular injury. In addition, AAV9-mediated Hmgcs2 silencing therapy improves tubular inflammatory injury and attenuates DKD progression. Taken together, this study unveils a tubule-macrophage metabolic crosstalk axis mediated by HMGCS2-driven AcAc accumulation, which couples mitochondrial stress to immune response in DKD.

Keywords:  Acetoacetate; Diabetic kidney disease; HMGCS2; Macrophage infiltration; Mitochondrial damage

DOI:  https://doi.org/10.1016/j.metabol.2026.156510
Cancer Discov. 2026 Jan 23. OF1

Breast Cancer Metastases Harbor Tissue-Specific Metabolic Dependencies.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2026-012
Life (Basel). 2026 Jan 20. pii: 171. [Epub ahead of print]16(1):

The Dual Anaplerotic Model (DAM): Integral Roles of Pyruvate Carboxylase and the GABA Shunt in Beta Cell Insulin Secretion.

Vladimir Grubelnik, Jan Zmazek, Marko Marhl.

  We present a simplified phenomenological computational framework that integrates the GABA shunt into established metabolic mechanisms underlying pancreatic beta cell insulin secretion. The GABA shunt introduces carbon into the tricarboxylic acid (TCA) cycle via succinate, thereby functioning as an anaplerotic pathway. This anaplerotic input is coupled to oscillatory cataplerotic fluxes, primarily involving α-ketoglutarate, whose effective extrusion requires coordinated counter-fluxes of malate and aspartate. Within the model, these cataplerotic exchanges are facilitated by UCP2-mediated transport processes and necessitate complementary anaplerotic replenishment through pyruvate carboxylase (PC). Based on this functional interdependence, we introduce the Dual Anaplerotic Model (DAM), which conceptually links two anaplerotic routes-the GABA shunt-mediated pathway and the glucose-dependent PC pathway-into a unified metabolic response module. DAM describes a coordinated, breathing-like redistribution of carbon between mitochondrial and cytosolic metabolite pools, while efficient oxidative metabolism of glucose-derived carbon entering the TCA cycle via pyruvate dehydrogenase is maintained. The model is driven by experimentally observed ATP/ADP and Ca2+ dynamics and is not intended to generate autonomous oscillations. Instead, it enables qualitative, phase-dependent visualization of how dual anaplerotic fluxes constrain and shape oscillatory metabolic states in beta cells. DAM provides an integrative conceptual scaffold for interpreting experimental observations and for motivating future quantitative modeling and experimental studies addressing metabolic regulation in physiological and pathophysiological contexts.

Keywords:  GABA shunt; PEP cycle; anaplerosis; beta cell oscillations; cataplerosis; mitochondrial metabolism

DOI:  https://doi.org/10.3390/life16010171
Metabolites. 2026 Jan 16. pii: 79. [Epub ahead of print]16(1):

Metabolomic Signatures of Recovery: A Secondary Analysis of Public Longitudinal LC-MS Datasets Shows Polyphenol-Rich Interventions Attenuate Purine Degradation and Oxidative Stress Following Exhaustive Exercise.

Xuyang Wang, Chang Liu, Yirui Chen, Mengyang Wang, Kai Zhao, Wei Jiang.

  Background: Post-exercise recovery involves coordinated metabolic restoration and redox rebalancing. Although dietary polyphenols have been proposed to facilitate recovery, the metabolic mechanisms underlying their effects-particularly during the recovery phase-remain insufficiently characterized. This study aimed to investigate how polyphenol supplementation modulates post-exercise metabolic recovery using an integrative metabolomics approach. Methods: We conducted a secondary analysis of publicly available longitudinal human LC-MS metabolomics datasets from exercise intervention studies with polyphenol supplementation. Datasets were obtained from the NIH Metabolomics Workbench and MetaboLights repositories; study-level metadata were used as provided by the original investigators. Global metabolic trajectories were assessed using principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Targeted analyses focused on purine degradation intermediates and redox-related metabolites. Correlation-based network and pathway enrichment analyses were applied to characterize recovery-phase metabolic reorganization. Results: Exercise induced a pronounced global metabolic perturbation in both placebo and polyphenol groups. During recovery, polyphenol supplementation was associated with a partial reversion of the metabolome toward the pre-exercise state, whereas placebo samples remained metabolically displaced. Discriminant metabolite analyses identified purine degradation intermediates and oxidative stress-related lipid species as key contributors to group separation during recovery. Polyphenol supplementation attenuated recovery-phase accumulation of hypoxanthine, xanthine, and uric acid and was associated with a sustained suppression of the uric acid-to-hypoxanthine ratio. Network analyses revealed weakened correlations between purine metabolites and oxidative stress markers, along with reduced network centrality of stress-responsive metabolic hubs. Conclusions: These findings indicate that polyphenol supplementation is associated with accelerated metabolic normalization during post-exercise recovery, potentially through modulation of purine-associated oxidative pathways and system-level metabolic network reorganization.

Keywords:  lipid peroxidation; network analysis; nutraceuticals; recovery kinetics; redox homeostasis; systems metabolomics; xanthine oxidase pathway

DOI:  https://doi.org/10.3390/metabo16010079
Res Pharm Sci. 2026 Feb;21(1): 96-109

The combination of rosuvastatin and meloxicam enhances the radiotherapy efficacy of MCF7, T-47D, and MDA-MB-231 breast cancer cell lines.

Arvin Naeimi, Hamid Saeidi Saedi, Amir Mohsen Bakhtiyari, Kimia Shabani, Zahra Babajani, Mona Haddad Zahmatkesh.

   Background and purpose: Radiotherapy is an essential treatment for breast cancer, but radioresistance remains a major obstacle. Studies suggest that statins and cyclooxygenase-2 (COX-2) inhibitors can enhance radiotherapy, yet few have examined their combined effects on breast cancer radiosensitivity. This study investigates the impact of meloxicam and rosuvastatin pretreatment on the radiosensitivity of MCF-7, T-47D, and MDA-MB-231 breast cancer cell lines.
Experimental approach: MCF-7, T-47D, and MDA-MB-231 cells were pretreated with varying concentrations of meloxicam, rosuvastatin, or both. Their response to radiation was evaluated using micronucleus, clonogenic, catalase, and superoxide dismutase (SOD) assays to assess chromosomal damage, cell survival, oxidative stress (via hydrogen peroxide degradation), and SOD antioxidant enzyme activity, respectively.
Findings/Results: Pretreatment with combined rosuvastatin (R) and meloxicam (M) at R2+M10 μM, R10+M50 μM, and R20+M100 μM increased genotoxicity and reduced colony formation across all irradiated cell lines compared to radiation alone. R10 μM, R10+M50 μM, and R20+M100 μM decreased catalase activity across irradiated cell lines compared to radiation alone, whereas R2+M10 μM decreased catalase activity significantly only in T-47D cells. Pretreatment with R10 μM, R2+M10 μM, R10+M50 μM, and R20+M100 μM reduced SOD activity in all irradiated cell lines compared to radiation alone.
Conclusion and implications: The combination of rosuvastatin and meloxicam at specific concentrations increased the radiation sensitivity of MCF-7, T-47D, and MDA-MB-231 cells. Combined pretreatment with rosuvastatin 10 μM and meloxicam 50 μM notably enhanced genotoxicity while reducing colony formation, catalase activity, and SOD activity compared to radiotherapy alone in MCF-7, T-47D, and MDA-MB-231 cell lines.

Keywords:  Breast cancer; MB-231; MCF7; Radiosensitization; Radiosensitizer; Radiotherapy; T47D

DOI:  https://doi.org/10.4103/RPS.RPS_191_24
Metabolites. 2026 Jan 08. pii: 54. [Epub ahead of print]16(1):

Metabolic Signatures of Breast Cancer Subtypes and the Metabolic Impact of Chemotherapy.

Aubrey Mattingly, Zoe Vickery, Alex Fiorentino, Ethan Wilson, Sydney McCune, Sydney Clark, Eric Blanchard, Jillian Spencer, Abigail Broom, Diana Ivankovic, Brooklyn Pace, Lauren Baskin, Ludovico Abenavoli, W Jeffery Edenfield, Ki Chung, Christopher L Farrell, Hakon Hakonarson, Luigi Boccuto.

  Background/Objectives: Breast cancer is a prevalent and heterogeneous disease with multiple subtypes, which are defined by characteristics such as molecular biomarkers and metastatic status. This study aimed to profile the metabolic activity of various breast cancer subtypes, both with and without chemotherapy (doxorubicin) application. Methods: Six human breast cell lines were evaluated, two non-tumorigenic controls and four cancerous lines. The cancer lines were clustered as primary-derived, metastasis-derived, triple-negative (TNBC), and strong hormone receptor-positive (ER+/PR+) and analyzed using the Biolog phenotype mammalian microarrays (PM-M1 to PM-M8) to assess metabolic activity via NADH production under a wide array of substrate parameters. Results: Unique metabolic profiles emerged across the subtypes and clusters; the TNBC and metastatic cells demonstrated enhanced utilization of glycolytic and anaerobic substrates consistent with the Warburg effect. The ER+/PR+ cells showed heightened glucose utilization and unique sensitivity to metabolic effectors and doxorubicin. Additionally, significant metabolic differences were observed in nucleoside and amino acid utilization between cancer and control cells, particularly in metastatic and TNBC lines. Conclusions: Our findings reveal the profound metabolic diversity among breast cancer subtypes and highlight distinct substrate dependencies for proliferation. The results additionally provide a framework for developing metabolic biomarkers and targeted therapies for chemotherapy resistance in breast cancer subtypes.

Keywords:  breast cancer; chemotherapy; hormone receptor-positive; metabolic profiling; metabolomics; metastatic; precision medicine; primary; therapeutic tailoring; triple-negative

DOI:  https://doi.org/10.3390/metabo16010054
Nat Commun. 2026 Jan 27. 17(1): 949

Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial.

Tim Kong, Alex Mabry, Maureen Highkin, Anthony Z Wang, Jeremy Hoog, Zhanfang Guo, Adrian Gonzales-Gonzales, Shana Thomas, Yingduo Song, Feng Gao, Mateusz Opyrchal, Lindsay Peterson, Foluso Ademuyiwa, Julie Margenthaler, Rebecca Aft, Katherine Glover-Collins, Leslie Nehring, Yu Tao, Souzan Sanati, Ian S Hagemann, Fouad Boulos, Matthew Holt, Li Ding, Wenge Zhu, Stephen T Oh, Jianxin Wang, Agnieszka K Witkiewicz, Erik S Knudsen, Ron Bose, Jason D Weber, Matthew Goetz, Donald Northfelt, Jingqin Luo, Cynthia X Ma.

CDK4/6 inhibitors (CDK4/6i) improve outcomes for estrogen receptor (ER) positive/HER2-negative breast cancers (BCs), yet intrinsic and acquired resistance exist. Here, we evaluated anastrozole in combination with palbociclib (ANA/PAL) in the NeoPalAna Endocrine-Resistant cohort (NCT01723774). Thirty-four patients with clinical stage II/III ER + /HER2- BCs resistant to standard neoadjuvant endocrine therapy (on-treatment Ki67 > 10%) received neoadjuvant ANA/PAL, with serial biopsies analyzed. The primary endpoint, complete cell cycle arrest (CCCA; Ki67C1D15 ≤ 2.7% at cycle 1, day 15), was achieved in 57.6% of patients (95%CI: 39.2-74.5%). Resistance to ANA/PAL (Ki67C1D15 > 10%) was associated with higher pre-treatment tumor grade, Ki67, and specific PAM50 subtypes. Resistant tumors demonstrated reduced ER signaling and upregulation of cell cycle, mTOR, interferon, JAK/STAT, and immune checkpoints. Additionally, a 33-gene signature that predicted neoadjuvant Ki67 response to ANA/PAL was prognostic in a metastatic validation cohort. These findings underscore dysregulated oncogenic pathways as potential resistance mechanisms and biomarkers of response to CDK4/6i.

DOI: https://doi.org/10.1038/s41467-026-68570-6
J Nutr Biochem. 2026 Jan 24. pii: S0955-2863(26)00017-3. [Epub ahead of print] 110275

A metabolic basis for motor deficits in mice lacking BCKDK.

Lingyi Zhu, Isha Kinjawadekar, Caleb Prempeh, Inna A Nikonorova, Emily T Mirek, Esther M Lopez, William O Jonsson, Jordan L Levy, Lin Wang, Xiaoxuan Li, Yeva Shamailova, Timothy J Stanek, Elizabeth M Snyder, Piyawan Bunpo, Robert A Harris, Shawn M Davidson, Ronald C Wek, Tracy G Anthony.

  Branched-chain α-amino acids (BCAAs) support protein synthesis and their oxidation is restrained by branched-chain α-keto acid dehydrogenase kinase (BCKDK). We previously observed that in the brains of Bckdk knockout (KO) mice, BCAAs fall while glutamate is preserved and other amino acids rise. We asked why this profile emerges and how it affects skeletal muscle versus brain during nutrient stress. Motor behavior, protein synthesis and nutrient signaling were compared in the skeletal muscle and brains of wildtype (WT) and Bckdk KO male mice. In addition, nitrogen delivery into brain from BCAAs was assessed using stable isotope tracing and mass spectrometry imaging. Bckdk KO showed normal grip strength but poor beam traversal and reduced wheel running during protein restriction. In skeletal muscle, leucine or protein-feeding stimulated and fasting suppressed mechanistic target of rapamycin complex 1 (mTORC1) signaling in both genotypes. Fasting reduced muscle protein synthesis in both strains without activating the integrated-stress response (ISR). In contrast, Bckdk KO brains exhibited ISR activation during fasting, and up-regulation of Atf4 and its target genes, including Slc7a5 mRNA. Tracer studies revealed lower serum [15N]-BCAA enrichment and diminished incorporation of BCAA-derived nitrogen into brain glutamate in Bckdk KO mice, despite unchanged total glutamate. Thus, in the nongrowing adult constitutive BCKDH activation limits BCAA-derived nitrogen delivery to brain and alters AA transporters as part of an adaptive ISR during nutrient scarcity. This creates a vulnerability in brain not observed in skeletal muscle. These data provide a metabolic basis for poor motor performance in Bckdk KO mice.

Keywords:  BCAAs; BCKDK; ISR; MALDI imaging; glutamate; neuromuscular coordination; stable isotope tracing; transamination

DOI:  https://doi.org/10.1016/j.jnutbio.2026.110275
Metabolites. 2026 Jan 09. pii: 60. [Epub ahead of print]16(1):

Mitochondrial Redox Vulnerabilities in Triple-Negative Breast Cancer: Integrative Perspectives and Emerging Therapeutic Strategies.

Alfredo Cruz-Gregorio.

  Breast cancer is a significant public health concern, with triple-negative breast cancer (TNBC) being the most aggressive subtype characterized by considerable heterogeneity and the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Currently, there are no practical alternatives to chemotherapy, which is associated with a poor prognosis. Therefore, developing new treatments for TNBC is an urgent need. Reactive oxygen species (ROS) and redox adaptation play central roles in TNBC biology. Targeting the redox state has emerged as a promising therapeutic approach, as it is vital to the survival of tumors, including TNBC. Although TNBC does not produce high levels of ROS compared to ER- or PR-positive breast cancers, it relies on mitochondria and oxidative phosphorylation (OXPHOS) to sustain ROS production and create an environment conducive to tumor progression. As a result, novel treatments that can modulate redox balance and target organelles essential for redox homeostasis, such as mitochondria, could be promising for TNBC, an area not yet reviewed in the current scientific literature, thus representing a critical gap. This review addresses that gap by synthesizing current evidence on TNBC biology and its connections to redox state and mitochondrial metabolism, with a focus on innovative strategies such as metal-based compounds (e.g., copper, gold), redox nanoparticles that facilitate anticancer drug delivery, mitochondrial-targeted therapies, and immunomodulatory peptides like GK-1. By integrating mechanistic insights into the redox state with emerging therapeutic approaches, I aim to highlight new redox-centered opportunities to improve TNBC treatments. Moreover, this review uniquely integrates mitochondrial metabolism, redox imbalance, and emerging regulated cell-death pathways, including ferroptosis, cuproptosis, and disulfidptosis, within the context of TNBC metabolic heterogeneity, highlighting translational vulnerabilities and subtype-specific therapeutic opportunities.

Keywords:  mitochondria; oxidative stress; redox state; redox therapeutics; triple negative breast cancer

DOI:  https://doi.org/10.3390/metabo16010060
Biomedicines. 2026 Jan 17. pii: 202. [Epub ahead of print]14(1):

Metabolic Landscape of Endometrial Cancer: Insights into Pathway Dysregulation and Metabolic Features.

Qing Yang, Xiaoli Tian, Min Hu, Wenjing Ma, Qingzhen Xie, Jingchun Liu, Li Hong.

  Background: Metabolic reprogramming is increasingly recognized as a hallmark of endometrial cancer, yet tissue-based metabolic signatures remain insufficiently defined. Methods: Untargeted metabolomics was performed on paired endometrial cancer (n = 10) and adjacent normal tissues (n = 10). Differential metabolites were identified through multivariate and univariate analyses. KEGG enrichment characterized altered pathways, while Random Forest and SVM were used for machine-learning-based feature prioritization. ROC analyses were conducted to evaluate the discriminative potential of selected metabolites. Results: 300 metabolites were significantly altered. Tumor tissues showed increased sphingolipid metabolism, glutathione metabolism, and arachidonic acid metabolism, alongside decreased bile acid, phenylalanine, and steroid biosynthesis. Machine learning converged on six key metabolites that demonstrate strong tissue-discriminative capacity. Conclusions: Endometrial cancer exhibits a distinct metabolic profile characterized by lipid remodeling and redox adaptation. The six metabolites identified through machine-learning-based analyses represent candidate metabolic features associated with endometrial cancer and provide a foundation for future mechanistic studies and validation in larger, independent cohorts.

Keywords:  endometrial cancer; machine learning; metabolism

DOI:  https://doi.org/10.3390/biomedicines14010202
Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2518372123

Subcellular mass spectrometry reveals proteome remodeling in an asymmetrically dividing (frog) embryonic stem cell.

Bowen Shen, Leena R Pade, Fei Zhou, Peter Nemes.

  Subcellular proteomics maps protein localization within restricted domains of a cell, complementing high-resolution imaging by expanding the number of proteins that can be profiled at once. Achieving this at depth from subcellular inputs remains challenging. Here, we advance microprobe capillary electrophoresis-mass spectrometry (CE-MS) with trapped ion mobility spectrometry and data-independent acquisition (diaPASEF) to quantify more than a thousand proteins from opposite poles of an asymmetrically dividing embryonic blastomere in live Xenopus laevis embryos. From ~200 pg of HeLa digest-approximately 80% of a cell-the technology identified 1,035 proteins with high reproducibility in quantification (coefficient of variation <15% across technical triplicates). With microprobe sampling in vivo, we quantified 808-1,022 proteins from opposite poles of the dorsal-animal (D1) blastomere before division, and we traced how these spatial distributions are retained or remodeled in the descendant D1.1 (neural-fated) and D1.2 (epidermal-destined) cells. To decouple subcellular distributions from dorsal-ventral axis cues, we perturbed patterning by ultraviolet ventralization. These results establish microprobe CE-MS for deep subcellular proteomics in intact embryos and reveal spatially distinct protein distributions during early fate specification. These spatial proteome differences appear consistent with early lineage tendencies yet precede and likely bias, rather than fix, later fate decisions that depend on gastrula-stage inductive signals.

Keywords:  Xenopus; blastomere; mass spectrometry; proteomics; subcellular

DOI:  https://doi.org/10.1073/pnas.2518372123