bims-cesirm 2026-03-08 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2026–03–08
24 papers selected by
Tigist Tamir, University of North Carolina

Analysis of isobaric quantitative proteomic data using TMT-Integrator and FragPipe computational platform.
Interplay between 7-ketocholesterol and tamoxifen shapes stress responses in breast cancer cells.
Fat promotes growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer.
Phosphoproteomic Insights into the Metabolic Reprogramming of Cell Growth and Lipid Accumulation in Mucor circinelloides.
Metabolism of Epigenetic Ribonucleosides Leads to Nucleolar Stress and Cytotoxicity.
High-throughput simultaneous quantification of glycopeptides and phosphopeptides enabled by 12-plex DiLeu isobaric tags and dual-functional Titanium(IV)-IMAC material.
Integrated multi-omics analysis reveals comprehensive metabolism-driven tumor heterogeneity and immune microenvironment in hepatocellular carcinomas.
Decreased Glucose Metabolism and Declined Chaperones Are Unique Features Required for the Survival of Senescent Fibroblasts and Pyruvate Dehydrogenase Is a Potent Senolytic Target.
Unraveling the αVβ5-GLUT5 axis in breast cancer: linking extracellular matrix signaling to fructose metabolism: a scoping review.
Connecting the cell cycle to lipid metabolism in cancer: Their reciprocal roles and opportunity for therapeutic exploitation.
Inhibition of FicD-mediated AMPylation and deAMPylation by isoprenoid diphosphates.
Splicing Factor SF3B4 Promotes Melanoma Migration via Splicing-dependent Regulation of Talin1.
Non-Reducing Proteomics Reveals Disulfide-Dependent Proteoform Remodeling Under Oxidative Stress.
Shp1 phosphatase regulates CXCR2 protein stability and IL8-mediated invasiveness in breast cancer.
Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.
Stochasticity in mammalian cell growth rates drives cell-to-cell variability independently of cell size and divisions.
Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy.
Stress-dependent growth in breast cancer arises from a mechano-osmotic coupling and cell-sizing checkpoint.
Intestinal stearoyl-CoA desaturase-2 is highly expressed and nutritionally regulated but dispensable for energy balance.
Comprehensive machine learning identifies anoikis signatures predicting therapeutic resistance and survival in gastric cancer.
Decoding d- and l-Amino Acids: Data-Driven Recognition of Enantiomers and Post-Translational Modifications via Quantum Tunneling.
Beyond cellular distress: reframing GDF15 as a lipid-sensitive metabolic signal.
Protocol for single-cell optimization objective and trade-off inference.

Nat Commun. 2026 Mar 02.

Analysis of isobaric quantitative proteomic data using TMT-Integrator and FragPipe computational platform.

Hui-Yin Chang, Yamei Deng, Ruohong Li, Dmitry Avtonomov, Bo Wen, Sarah E Haynes, Felipe da Veiga Leprevost, Bing Zhang, Fengchao Yu, Alexey I Nesvizhskii.

Isobaric mass tags, such as isobaric tags for relative and absolute quantitation (iTRAQ) and tandem mass tag (TMT), are widely utilized for peptide and protein quantification in multiplex quantitative proteomics. We present TMT-Integrator, a bioinformatics tool for processing quantitation results from TMT and iTRAQ experiments, offering integrative reports at the gene, protein, peptide, and post-translational modification site levels. We demonstrate the versatility of TMT-Integrator using five publicly available TMT datasets: clear cell renal cell carcinoma (ccRCC) whole proteome and phosphoproteome datasets from the Clinical Proteomic Tumor Analysis Consortium, an E. coli dataset with 13 spike-in proteins, and two human cell lysate datasets showcasing the latest advances with the Thermo Orbitrap Astral mass spectrometer and TMTpro 35-plex reagents. Integrated into the widely used FragPipe computational platform (https://fragpipe.nesvilab.org/), TMT-Integrator is a core component of TMT and iTRAQ data analysis workflows. We evaluated the performance of FragPipe coupled with TMT-Integrator analysis pipeline against MaxQuant and Proteome Discoverer with multiple benchmarks, facilitated by the bioinformatics tool OmicsEV. Our results show that FragPipe coupled with TMT-Integrator quantifies more proteins in the E. coli and ccRCC whole proteome datasets, quantifies more phosphorylated sites in the ccRCC phosphoproteome dataset, and overall delivers more robust quantification performance compared to other tools.

DOI: https://doi.org/10.1038/s41467-026-70118-7
J Steroid Biochem Mol Biol. 2026 Mar 01. pii: S0960-0760(26)00043-9. [Epub ahead of print]260 106977

Interplay between 7-ketocholesterol and tamoxifen shapes stress responses in breast cancer cells.

Karolina Seborova, Kamila Koucka, Tereza Tesarova, Michaela Kurucova, Marie Ehrlichova, Petr Holy, Viktor Hlavac, Pavel Soucek, Alzbeta Spalenkova.

  7-ketocholesterol (7-KC) is a highly abundant and biologically active lipid oxidation product that perturbs membrane integrity, sterol homeostasis, mitochondrial function, and redox balance. In parallel, tamoxifen, a cornerstone therapy for estrogen receptor-positive breast cancer, induces not only estrogen receptor antagonism but also pronounced metabolic and organelle-associated stress. Here, we investigated transcriptional responses of breast cancer cell line models to tamoxifen, 7-KC, and their combination. Tamoxifen elicited a shared antiproliferative response in MCF-7 and BT-20 cells, characterized by suppression of cell cycle progression, DNA replication, and mitosis. However, the downstream stress responses diverged markedly between the two models. MCF-7 cells activated adaptive programs, including unfolded protein response, autophagy, and metabolic reprogramming toward glycolysis, consistent with cytostatic survival. In contrast, BT-20 cells exhibited suppression of metabolic and redox pathways accompanied by inflammatory and apoptotic signaling, indicating impaired stress adaptation. Combined tamoxifen and 7-KC treatment further amplified these divergent stress-response phenotypes. Analysis of the correlation of 16 oppositely regulated genes with clinical data of breast cancer patients validated ST8SIA6 as the main candidate associated with adaptive stress tolerance. Overall, our findings indicate that the capacity to integrate metabolic and redox stress determines tumor cell type-specific responses to combined endocrine and oxysterol-induced stress in breast cancer.

Keywords:  7-ketocholesterol; Breast cancer; Metabolic reprogramming; Oxidative stress; Tamoxifen

DOI:  https://doi.org/10.1016/j.jsbmb.2026.106977
APL Bioeng. 2026 Mar;10(1): 016111

Fat promotes growth and invasion in a 3D microfluidic tumor model of triple-negative breast cancer.

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

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

DOI: https://doi.org/10.1063/5.0291646
J Agric Food Chem. 2026 Mar 05.

Phosphoproteomic Insights into the Metabolic Reprogramming of Cell Growth and Lipid Accumulation in Mucor circinelloides.

Xinyi Zan, Jun Shen, Yihe Wang, Lina Zhao, Lei Sun, Wenjing Sun, Yuanda Song, Fengjie Cui.

  Mucor circinelloides is a model oleaginous fungus for studying microbial lipid accumulation, yet the post-translational mechanisms coordinating growth and lipid biosynthesis remain poorly understood. Here, we present the first systematic quantitative phosphoproteomic analysis of M. circinelloides across its life cycle, encompassing spores and mycelia at 6 h, 24 h (nitrogen depletion), and 96 h. A total of 1252 phosphoproteins and 1682 phosphopeptides were identified, revealing a phosphorylation-driven transition from growth-associated processes to lipid metabolism under nitrogen limitation. Dynamic phosphorylation of key enzymes, notably ATP-citrate lyase (ACL) and Acyl-CoA synthetase (ACS), directly mediated carbon flux redirection toward fatty acid synthesis. A conserved serine-rich motif in ACL suggests an evolutionarily conserved regulatory strategy for lipid accumulation. Integration with fluxomics and proteomics reveals a hierarchical network linking signaling, enzyme phosphorylation, and metabolic reprogramming. These findings provide new insights into phosphorylation-based regulation of fungal growth and lipid biosynthesis in oleaginous fungi.

Keywords:  lipid accumulation; metabolic reprogramming; phosphoproteomics; phosphorylation

DOI:  https://doi.org/10.1021/acs.jafc.6c00321
ACS Chem Biol. 2026 Mar 06.

Metabolism of Epigenetic Ribonucleosides Leads to Nucleolar Stress and Cytotoxicity.

Xuemeng Sun, Anita Donlic, Jacob A Boyer, Theodore E Press, Minjae Kim, Neal K Reddy, Clifford P Brangwynne, Joshua D Rabinowitz, Ralph E Kleiner.

Post-transcriptional RNA modifications are ubiquitous in biology, but the fate of epigenetic ribonucleotides after RNA turnover and the consequences of their metabolism and misincorporation into nucleic acids are largely unknown. Here, we explore epigenetic ribonucleoside metabolism in human cells by studying effects on cell growth, quantifying RNA misincorporation and identifying metabolic regulators, and exploring phenotypes associated with cytotoxicity. We find that bulky N6-modified adenosines (i.e., i6A) exhibit high levels of cytotoxicity and RNA misincorporation, whereas cells dramatically restrict the misincorporation of small N6-modified adenosines (i.e., m6A), partly through sanitization by enzymatic deamination, consistent with a recent report. Epigenetic ribopyrimidines also exhibit cytotoxicity, dependent on nucleoside kinase UCK2, but only at much higher concentrations than ribopurines. We further characterize the effects of cytotoxic ribonucleoside metabolism on nucleolar morphology and protein translation. Taken together, our work provides new insights into the metabolism of epigenetic ribonucleosides and mechanisms underlying their cytotoxicity to cells.

DOI: https://doi.org/10.1021/acschembio.5c00656
Anal Chim Acta. 2026 Apr 15. pii: S0003-2670(26)00181-9. [Epub ahead of print]1395 345231

High-throughput simultaneous quantification of glycopeptides and phosphopeptides enabled by 12-plex DiLeu isobaric tags and dual-functional Titanium(IV)-IMAC material.

Feixuan Wu, Danqing Wang, Dylan Nicholas Tabang, Peng-Kai Liu, Zicong Wang, Yuan Liu, Angelique Steenhagen, Luigi Puglielli, Lingjun Li.

   BACKGROUND: Protein glycosylation and phosphorylation are critical post-translational modifications (PTMs) that regulate diverse physiological and pathological processes, yet their comprehensive characterization remains challenging due to low abundance and poor ionization efficiency. Recent advances using epoxy-ATP-Ti4+-IMAC materials have enabled simultaneous enrichment of N-glycopeptides, phosphopeptides, and mannose-6-phosphate glycopeptides. However, high-throughput, multiplexed quantification of these PTMs is still lacking. This work addresses the need for an efficient strategy capable of simultaneously enriching, identifying, and quantitatively comparing glycosylation and phosphorylation across multiple biological samples.
RESULTS: We developed a high-throughput workflow integrating epoxy-Ti4+-IMAC enrichment with custom N,N-dimethyl leucine (DiLeu) isobaric tags to achieve 12-plex quantitative analysis of N-glycosylation and phosphorylation for the first time. This streamlined one-tube sample preparation protocol enabled robust, simultaneous enrichment and quantification of PTMs from complex mouse brain samples. Application to APP/PS1 transgenic mice versus wild-type controls produced quantitative identification of 1975 N-glycopeptides and 1181 phosphopeptides. Comparative profiling revealed substantial PTM alterations associated with Alzheimer's disease (AD)-related pathology. Differentially modified proteins mapped to key biological pathways, including synapse organization, synaptic membrane regulation, and cell adhesion. The abundance patterns highlighted broad disruptions in PTM-mediated signaling and provided molecular insights into synaptic dysfunction in the APP/PS1 model.
SIGNIFICANCE AND NOVELTY: This integrated DiLeu isobaric labeling-epoxy-Ti4+-IMAC platform provides a powerful, high-throughput solution for the simultaneous quantification of glycosylation and phosphorylation, enabling detailed investigation of PTM interplay. By uncovering disease-associated modifications in AD mouse models, this method offers new opportunities to identify mechanistic biomarkers and therapeutic targets. Its versatility and scalability make it broadly applicable to PTM-centric studies across diverse biological systems, including biofluids, cell lysates and tissues.

Keywords:  Enrichment; Glycoproteomics; High-throughput isobaric tagging for quantitation; Immobilized metal affinity chromatography; Phosphoproteomics; Post-translational modifications

DOI:  https://doi.org/10.1016/j.aca.2026.345231
Sci Rep. 2026 Mar 04.

Integrated multi-omics analysis reveals comprehensive metabolism-driven tumor heterogeneity and immune microenvironment in hepatocellular carcinomas.

Yu Li, Zihan Luo, Bingyu Zhang, Wenyao Zhu, Jinlian Zhang, Zizhao Li, Lingyu Zhang.



Keywords:  Epigenetic reprogramming; Hepatocellular carcinoma; Metabolic reprogramming; Multi-Omics integration; Post-translational modification

DOI:  https://doi.org/10.1038/s41598-026-42856-7
Aging Cell. 2026 Mar;25(3): e70434

Decreased Glucose Metabolism and Declined Chaperones Are Unique Features Required for the Survival of Senescent Fibroblasts and Pyruvate Dehydrogenase Is a Potent Senolytic Target.

Mingzhu Zhang, Ziqi Hu, Shengwen Piao, Yingrui Song, Ying Jia, Jiaxing Liu, Ning Zhao, An Liu, Songbin Fu, Wenjing Sun, Hui Xu, Yu Yang, Steven P Gygi, Chunshui Zhou.

  Cellular senescence contributes to aging and age-related diseases. Deep identifications of the senescence-specific cellular features are crucial to the better understanding of the survival and maintenance of senescence and the development of novel senolytics against senescent cells. By a global proteomic profiling of senescent human BJ fibroblasts induced by ionizing radiation, 178 cellular proteins with at least 4-fold or greater changes in abundance were identified, representing the cellular landscape of the senescent fibroblasts. Functional enrichments and biological experiments demonstrated that the decreased glucose metabolism, reduced ATP and alpha-KG production, and declined chaperones are the most striking features associated with senescent fibroblasts. Moreover, these proteomic features are closely correlated with their transcription alterations confirmed by RT-PCR. Respectively, inhibiting pyruvate dehydrogenase (critical enzyme to supply acetyl-CoA to TCA cycle) or glutaminase GLS1 (crucial enzyme to supplement TCA cycle intermediate alpha-KG) or inhibiting Hsp90 (important member of chaperones) led to the selective killing of senescent fibroblasts, indicating the essential roles of the TCA cycle or chaperones in the survival and maintenance of cellular senescence. Most importantly, co-inhibiting the TCA cycle and Hsp90 gave rise to the enhanced selective killing of senescent fibroblasts as well as the therapy-induced senescent cancer cells and the alleviation of physical dysfunctions in aged mice, suggesting the synergistic regulation of cellular senescence by the TCA cycle and chaperones. Thus, our profiling revealed key cellular features for the survival and maintenance in senescent normal cells, demonstrating that pyruvate dehydrogenase is a novel and potent senolytic target for the selective elimination of senescence.

Keywords:  cellular senescence; chaperones; glucose metabolism; pyruvate dehydrogenase; senolytics; therapy‐induced senescence

DOI:  https://doi.org/10.1111/acel.70434
Mol Biol Rep. 2026 Mar 03. pii: 449. [Epub ahead of print]53(1):

Unraveling the αVβ5-GLUT5 axis in breast cancer: linking extracellular matrix signaling to fructose metabolism: a scoping review.

Rahul S Tade, Dilip L Pawara, Pravin O Patil, Prashant B Patil.



Keywords:  Breast cancer; Extracellular signaling; Fructose metabolism; GLUT5; Integrin αVβ5; Metabolic reprogramming; Targeted therapy

DOI:  https://doi.org/10.1007/s11033-026-11621-4
Mol Cancer Res. 2026 Mar 03.

Connecting the cell cycle to lipid metabolism in cancer: Their reciprocal roles and opportunity for therapeutic exploitation.

Joshua T Hodgson, Lisa M Butler, Margaret M Centenera.

Uncontrolled cellular proliferation is a hallmark of cancer that is both driven by deregulation of the cell cycle, and fueled by metabolic reprogramming. Among the metabolic alterations detected, lipid metabolism is markedly upregulated to provide resources for proliferating cancer cells. Each cell cycle requires lipids for membrane synthesis, energy production, and cellular signaling, yet the mechanistic relationship linking the cell cycle to lipid metabolism in cancer remains incompletely understood. Recent advances in lipidomic technologies that enable comprehensive profiling of the cancer lipidome have provided new insights into the interconnections between these two pathways. This review describes how cell cycle regulators influence various aspects of lipid metabolism in models of cancer and the effect of cell cycle perturbation on cellular lipid profiles. We further describe lipid metabolic changes associated with response and resistance to cell cycle inhibitors in cancer and offer insight into how these findings may inform the development of clinical biomarkers and new therapeutic strategies.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-1270
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2533457123

Inhibition of FicD-mediated AMPylation and deAMPylation by isoprenoid diphosphates.

Aubrie M Blevins, Wei Peng, Lisa N Kinch, Zihan Monshad, Andrea G Paredes, Christina Volz, Jared Rutter, Amanda K Casey, Kevin G Hicks, Kim Orth.

  FicD regulates Unfolded Protein Response (UPR) through reversible AMPylation and deAMPylation of BiP, an HSP70 chaperone and master regulator of the UPR. FicD activity is regulated by endoplasmic reticulum-stress, catalyzing BiP AMPylation under low stress conditions to hold inactive chaperone in reserve. In stressed cells, FicD deAMPylates BiP, acutely increasing its active pool to assist in protein folding. Variants in UPR machinery, including those in the FicD gene, are linked to hereditary diseases. Despite the known role of FicD in UPR, in-vivo regulation of its activity remains elusive, and identifying metabolites that alter FicD activity could prove useful pharmaceutically. We applied an unbiased high-throughput screening platform, known as Mass spectrometry Integrated with equilibrium Dialysis for the discovery of Allostery Systematically (MIDAS), to identify small molecule metabolites that might regulate FicD activity. MIDAS revealed interactions between FicD and two mevalonate pathway intermediates: geranyl-pyrophosphate and farnesyl-pyrophosphate. Biochemical characterization indicates that both potently inhibit FicD-mediated AMPylation and deAMPylation. The crystal structure of FicD bound to farnesyl-pyrophosphate demonstrates a competitive inhibition mechanism, with the pyrophosphate adopting the alpha and beta phosphate positions of adenosine triphosphate (ATP) and the hydrocarbon chain filling the nucleoside pocket. FicD variants previously appeared as biochemically indistinguishable, yet lead to different human pathologies. We demonstrate farnesyl-pyrophosphate inhibits FicDR374H and FicDR374C variants implicated in causing hereditary spastic paraplegia, but not the FicDR371S variant associated with neonatal diabetes. This study furthers our understanding of FicD inhibitors and distinguishes disease causing variants, providing insight into pharmacological targeting of UPR activity.

Keywords:  AMPylation; FicD; PTM; isoprenoid diphosphates; unfolded protein response

DOI:  https://doi.org/10.1073/pnas.2533457123
Cancer Genomics Proteomics. 2026 Mar-Apr;23(2):23(2): 233-243

Splicing Factor SF3B4 Promotes Melanoma Migration via Splicing-dependent Regulation of Talin1.

Seungmin Shin, Minbeom Ko, Wei Zhang, Seung Min Jeong.

   BACKGROUND/AIM: Melanoma is a highly aggressive cancer in which metastatic dissemination remains the primary cause of mortality. This study aimed to define the role of the splicing factor 3b subunit 4 (SF3B4) in melanoma progression and its downstream regulatory mechanisms.
MATERIALS AND METHODS: SF3B4 expression was analyzed in public datasets. Its functional role was assessed by knockdown or inhibition in melanoma cells using proliferation, wound healing, and transwell assays. Talin1 expression and splicing were evaluated by RT-qPCR and immunoblotting, and FAK phosphorylation was measured as a downstream readout.
RESULTS: SF3B4 is significantly upregulated in melanoma, particularly in metastatic lesions, and its expression correlates with poor patient survival. SF3B4 depletion suppresses melanoma cell growth and migration. Talin1 was identified as a downstream target of SF3B4, as SF3B4 knockdown reduced Talin1 mRNA and protein levels and impaired its splicing, leading to increased intron retention. Consistently, SF3B4 loss reduced phosphorylation of focal adhesion kinase (FAK), indicating attenuation of Talin1-mediated signaling. Talin1 knockdown recapitulated the migration defects observed upon SF3B4 depletion, and combined knockdown showed no additive effect, supporting a shared regulatory pathway.
CONCLUSION: SF3B4 promotes melanoma cell migration through splicing-dependent regulation of Talin1. The SF3B4-Talin1 axis represents a potential therapeutic target in metastatic melanoma.

Keywords:  SF3B4; Talin1; cell migration; melanoma; splicing

DOI:  https://doi.org/10.21873/cgp.20574
Mol Cell Proteomics. 2026 Mar 02. pii: S1535-9476(26)00044-7. [Epub ahead of print] 101548

Non-Reducing Proteomics Reveals Disulfide-Dependent Proteoform Remodeling Under Oxidative Stress.

Yeonjoo Lee, Tae-Kyung Kim, Seungjin Na, Kong-Joo Lee, Jaeho Jeong, Eun Joo Song.

Oxidative stress triggers redox-sensitive post-translational modifications, notably disulfide bond formation involving cysteine residues. However, these bonds are often overlooked in proteomics due to the routine use of reducing agents. Here, we employed liquid chromatography-mass spectrometry (LC-MS) based metabolomics and non-reducing tandem mass tag (TMT) proteomics to investigate the effects of H2O2 on MDA-MB-231 cells. Metabolomic analysis revealed pathway-specific inhibition of major metabolic pathways including glycolysis, the tricarboxylic acid (TCA) cycle, and nucleotide biosynthesis. Proteomic analysis using the DBond algorithm revealed extensive and isoform-specific disulfide crosslinks across more than 1,000 proteins. These linkages were enriched at redox-sensitive cysteines near basic residues and displayed high isoform specificity. Our findings demonstrate that disulfide bond formation serves as a selective mechanism of redox regulation. This study highlights the utility of non-reducing proteomics in elucidating redox-controlled protein networks and structural dynamics under oxidative stress.

DOI: https://doi.org/10.1016/j.mcpro.2026.101548
Cell Death Dis. 2026 Mar 02.

Shp1 phosphatase regulates CXCR2 protein stability and IL8-mediated invasiveness in breast cancer.

Marcello Monti, Pier Giorgio Amendola, Angela Filograna, Sabrina Gargiulo, Marcello Allegretti, Daniela Corda, Alessia Varone.

Shp1 is a cytosolic tyrosine phosphatase generally associated with antitumor effects through the inhibition of tyrosine kinase signaling. Herein, we shown that genetic and pharmacological inhibition of Shp1 in breast cancer cells induces accelerated cell migration and promotes a more invasive phenotype. Furthermore, we found that interleukin-8 (IL8), a chemokine with multiple pro-tumorigenic roles within the tumor microenvironment, directly modulates Shp1 activity. In breast cancer, IL8 elicits its functions through the binding to the CXCR2 receptor with the subsequent modulation of several intracellular signaling pathways. We show that in breast MCF7 cells, IL8 induces the PKC-mediated phosphorylation of Shp1 at Ser591, diminishing its enzymatic activity and impairing the dephosphorylation of PP2A; this enhances CXCR2 phosphorylation and alters receptor trafficking by promoting ubiquitination and degradation of CXCR2. This feedback mechanism limits IL8 signaling revealing a previously unrecognized mechanism of receptor turnover and signal attenuation. In addition, we found that Shp1-mediated regulation of CXCR2 directly influences IL8-driven invasiveness in a subtype-specific manner, affecting luminal and triple-negative breast cancer (TNBC) cells but not HER2-positive ones. Transcriptomic and pathway analyses further support Shp1 involvement in cytokine and GPCR signaling, particularly in TNBC, where its downregulation correlates with reduced survival and higher IL8 levels. Taken together, our findings elucidate a novel mechanism of IL8 signaling and identify Shp1 as a promising therapeutic target, highlighting the potential of modulating the CXCR2-Shp1 axis to limit invasiveness and metastasis in aggressive breast cancer subtypes, particularly TNBC.

DOI: https://doi.org/10.1038/s41419-026-08516-4
Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]

Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.

Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.

  The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.

Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response

DOI:  https://doi.org/10.1016/j.cell.2026.01.028
Cancer Res. 2026 Mar 02. 86(5): 1095-1097

Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.

Mohammadreza Alizadeh-Ghodsi, Andrew S Goldstein.

Prostate cancer progression is predominantly driven by androgen receptor (AR) signaling, and despite initial benefits of androgen deprivation therapy (ADT), most patients eventually develop lethal castration-resistant disease. Cyclic administration of supraphysiologic androgen (SPA) with ADT paradoxically suppresses tumor growth; however, responses are heterogeneous, and the mechanisms underlying the antitumor effects of SPA remain incompletely understood. In this issue of Cancer Research, Kumar and colleagues demonstrate that SPA induces a distinct metabolic response, characterized by AR-dependent induction of polyamine biosynthesis via ODC1 and AMD1. This metabolic rewiring elevates polyamine synthesis while concurrently depleting the methyl donor S-adenosylmethionine (SAM). Although increased polyamine metabolism by SPA may promote adaptive resistance, genetic or pharmacologic inhibition of ODC1 using difluoromethylornithine (DFMO) enhances SPA-induced growth suppression by disrupting protective polyamine pools and further exacerbating SAM depletion, revealing a metabolic vulnerability in SPA-treated prostate cancer cells. Supporting these findings, a clinical trial combining DFMO with bipolar androgen therapy (BAT) demonstrated reduced circulating polyamines in patients, confirming polyamine pathway suppression in patients with different genomic features. Together, this study uncovers a mechanistic link among androgen signaling, polyamine metabolism, and therapeutic response, providing a rationale for targeting metabolic dependencies to improve SPA efficacy. See related article by Kumar et al., p. 1148.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4807
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2516372123

Stochasticity in mammalian cell growth rates drives cell-to-cell variability independently of cell size and divisions.

Ethan Levien, Joon Ho Kang, Kuheli Biswas, Scott R Manalis, Ariel Amir, Teemu P Miettinen.

  Cell growth rates exhibit cell-intrinsic cell-to-cell variability, which influences cell fitness and size homeostasis from bacteria to cancer. It remains unclear whether this variability arises from stochasticity in cell growth or division processes, or from cell-size-dependent growth regulation. To separate these potential sources of growth variability, single-cell growth rates need to be examined across different timescales. Here, we study cell size and growth regulation by tracking lymphocytic leukemia cell mass accumulation with high precision and minute-scale temporal resolution along long ancestral lineages. We first show that correlations between growth rates and cell-size nor asymmetric divisions explain cell-to-cell growth variability. We then isolate growth fluctuations by smoothing and detrending the growth rate dynamics using a Gaussian process regression. We find that these growth fluctuations drive cell-to-cell growth variability within ancestral lineages despite being independent of cell divisions, cell cycle, and cell size. Overall, our results provide a quantitative framework for understanding single-cell growth rates, and indicate that cell-intrinsic long-term patterns in growth are a byproduct of short-term growth fluctuations.

Keywords:  cell divisions; cell growth; cell size; cellular noise; heterogeneity

DOI:  https://doi.org/10.1073/pnas.2516372123
Cell Rep. 2026 Mar 05. pii: S2211-1247(26)00139-7. [Epub ahead of print]45(3): 117061

Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy.

Garrett F Beeghly, Irina Kopyeva, Jenny Deng, Marlee I Pincus, Rohan R Varshney, Dilip D Giri, Domenick J Falcone, Michael C Rudolph, Marc A Antonyak, Neil M Iyengar, Claudia Fischbach.

  Primary adipocytes exhibit striking variability in size, yet the functional consequences of adipocyte hypertrophy remain unclear due to insufficient experimental approaches to control for cell size. Here, we establish methods to culture large and small primary adipocytes isolated from the same adipose depot, enabling size-resolved analyses independent of systemic obesity. Using transcriptomic, lipidomic, and functional profiling across two mouse models of obesity, as well as human clinical samples, we show that adipocyte size-rather than body weight-drives distinct phenotypic cell states. Notably, large adipocytes increase extracellular vesicle-mediated lipid release. In coculture assays, this shift enhances lipid uptake, migration, and proliferation of breast cancer cells through fatty acid oxidation. Consistent with these findings, individuals with larger mammary adipocytes exhibit elevated fasting triglycerides independent of body mass index. Together, our results identify adipocyte size as a key determinant of adipose tissue function with implications for both metabolic disease and cancer progression.

Keywords:  CP: cancer; CP: metabolism; adipocyte; adipose tissue; breast cancer; extracellular vesicles; hypertrophy; lipid metabolism; obesity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2026.117061
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2523159123

Stress-dependent growth in breast cancer arises from a mechano-osmotic coupling and cell-sizing checkpoint.

Irish Senthilkumar, Jef Vangheel, Vatsal Kumar, Laoise McNamara, Bart Smeets, Enda Howley, Eoin McEvoy.

  Mechanoresponsive cell proliferation is a feature of growing tumors, despite the suppression of many other regulatory checkpoints in cancer, but the underlying cell-scale mechanisms driving this behavior have not yet been established. In this study, we propose a biophysical model for cell growth as governed by actively controlled osmolarity, which we integrate with a discrete particle framework to simulate growth and remodeling of breast cancer spheroids. Confinement and biomechanical feedback from the extracellular environment are analyzed through a neural-network-accelerated finite element solver. Combining the framework with experiments, our model reveals that stress-dependent spheroid growth can arise from a sizing checkpoint for mitosis. Under sufficient extracellular loading, cell growth is restricted by high hydrostatic forces in competition with osmotic pressure from biomolecule synthesis, which prevents cells from surpassing a critical volume. Our model provides insight into mechanosensitive growth arrest in breast cancer, potentially serving as a computational tool for analyzing growth in a wider range of normal and malignant biological tissues.

Keywords:  cancer mechanobiology; discrete cell modeling; stress-dependent growth

DOI:  https://doi.org/10.1073/pnas.2523159123
Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Mar 03. pii: S1388-1981(26)00021-1. [Epub ahead of print] 159735

Intestinal stearoyl-CoA desaturase-2 is highly expressed and nutritionally regulated but dispensable for energy balance.

Matthew Selby, Camille Duchamp, Natalie Burchat, Priyanka Sharma, Guojun Wu, Lakshmi Gayathri Pantula, Archini Desai, Makoto Miyazaki, Harini Sampath.

  The stearoyl-CoA desaturase (SCD) enzymes convert saturated fatty acids to monounsaturated fatty acids (MUFAs). Deletion of intestinal SCD1 confers metabolic benefits upon high-fat diet (HFD) feeding. We report here that mice express a second SCD isoform in the intestine. SCD2 is expressed at much greater levels than SCD1 along the small intestine and colon. SCD2 displays spatial enrichment in the distal small intestine and in the colon and nutritional regulation by dietary fat and sucrose. Deletion of intestinal SCD2 (in 2iKO mice) reduces colonic, hepatic, and plasma triglycerides. However, MUFA levels and desaturation ratios are largely unimpacted in 2iKO intestines. SCD2 deletion is accompanied by upregulation of SCD1 and the fatty acid transporter, CD36, which together may help retain MUFA balance in the gut. Consistent with a lack of impact on MUFA levels, deletion of SCD2 does not protect mice from HFD-induced metabolic dysfunction. However, upon sucrose refeeding, SCD2 deletion blunts hepatic lipogenesis and triglyceride accumulation, suggesting that intestinal SCD2 modulates interorgan communication under conditions of carbohydrate overfeeding. While SCD1 and CD36 likely help retain MUFA balance in 2iKO mice intestines, primary organoids cultured ex vivo indicate significant reductions in overall desaturase activity in 2iKO organoids, despite increases in Scd1 expression. 2iKO organoids do not, however, induce Cd36 expression, and this is accompanied by a significant induction of ER stress in 2iKO organoids. Together, these data reveal a novel role for intestinal SCD2 in maintaining cellular MUFA balance to modulate responses to nutrient overload and to prevent ER stress.

Keywords:  Colon lipidomics; Gut-liver crosstalk; Intestinal lipid metabolism; Nutrient response; Single-cell RNA-Seq

DOI:  https://doi.org/10.1016/j.bbalip.2026.159735
Sci Rep. 2026 Mar 02.

Comprehensive machine learning identifies anoikis signatures predicting therapeutic resistance and survival in gastric cancer.

Fangchao Liu, Yaoyao Zhou, Yongjie Xie, Ziyi Dong, Chenghuan Dao, Jiahe Wang, Yuan Li, Yaoyang Guo, Zhanyu Pan, Feng Liang.



Keywords:  Anoikis; Drug resistance; Gastric cancer; Immune microenvironment and immunotherapy; Machine learning

DOI:  https://doi.org/10.1038/s41598-026-38996-5
J Phys Chem Lett. 2026 Mar 04.

Decoding d- and l-Amino Acids: Data-Driven Recognition of Enantiomers and Post-Translational Modifications via Quantum Tunneling.

Sneha Mittal, Milan Kumar Jena, Biswarup Pathak.

Single molecule identification of d- and l-amino acid enantiomers is highly desirable but challenging due to subtle chemical differences, dynamic interconversion, and the coexistence of numerous post-translational modifications (PTMs). Notably, proteomics has not yet achieved the level of precision seen in genomics and transcriptomics, largely because existing methods struggle to resolve chirality-specific molecular signatures within complex proteomes. Here, we combine a data-driven machine learning approach with quantum tunneling to screen and detect d/l-isomers and PTMs, including isobaric isomers, methylation, phosphorylation, and ring formation. Our ML framework should be distinguished from ML-for-materials paradigms focused on replacing expensive quantum calculations or learning transferable descriptors. Instead, it serves as a decision-theoretic layer that maps high-dimensional, precomputed quantum tunneling features to biochemical labels, addressing the analytical challenge of signal disambiguation rather than computational acceleration. Our work illustrates a systematic and internally consistent physics-based simulation framework for identification of amino acid d/l-isomers and variants and thus opens frontiers in challenging single-molecule protein sequencing.

DOI: https://doi.org/10.1021/acs.jpclett.6c00203
Curr Opin Lipidol. 2026 Apr 01. 37(2): 45-51

Beyond cellular distress: reframing GDF15 as a lipid-sensitive metabolic signal.

Dongdong Wang, Logan K Townsend, Gregory R Steinberg.

   PURPOSE OF REVIEW: Growth differentiation factor-15 (GDF15) is widely described as a hormone that conveys somatic distress to the brain, yet this framework does not explain why GDF15 is elevated in many common metabolic states. Recent work shows that GDF15 rises most consistently when fatty acid availability exceeds mitochondrial and endoplasmic reticulum capacity. This review synthesizes emerging evidence that positions GDF15 as an endocrine sensor of lipid load rather than a general stress signal.
RECENT FINDINGS: Across acute dietary lipid exposure, endogenous lipolysis during fasting, chronic overnutrition, ketogenic feeding, and mitochondrial dysfunction, free fatty acids activate lipid-sensitive transcriptional pathways that induce GDF15 expression in kidney, liver, intestine, and adipose tissue macrophages. Once elevated, GDF15 engages hindbrain glial-cell-derived neurotrophic factor family receptor α-like (GFRAL) signaling to increase sympathetic outflow, promote whole-body fatty acid oxidation, redistribute lipid burden, and improve metabolic flexibility. These effects occur independently of reduced food intake and reflect coordinated actions across liver, adipose tissue, and skeletal muscle.
SUMMARY: Viewing GDF15 as a lipid-responsive hormonal signal reshapes our understanding of its physiological role and provides new insight into metabolic adaptations to lipid overload. This pattern suggests that GDF15 is part of a feedback system that attempts to match fatty acid oxidation with supply, analogous to how carbohydrate ingestion stimulates insulin to promote glucose oxidation and suppress hepatic glucose production to restore euglycemia. Within this framework, individual tissues respond in complementary ways to reduce lipid burden and maintain metabolic balance. Understanding this coordinated lipid-responsive network highlights opportunities to target the GDF15 pathway in disorders characterized by impaired fatty acid handling including obesity, type 2 diabetes, cardiovascular disease, cancer cachexia and metabolic dysfunction-associated steatotic liver disease (MASLD).

Keywords:  GFRAL; MASH; MASLD; adipose tissue; diabetes; fatty acids; growth differentiation factor-15; lipotoxicity; mitochondrial stress; triglycerides

DOI:  https://doi.org/10.1097/MOL.0000000000001025
STAR Protoc. 2026 Mar 05. pii: S2666-1667(26)00026-2. [Epub ahead of print]7(1): 104373

Protocol for single-cell optimization objective and trade-off inference.

Da-Wei Lin, Cara Teixeira, Carolina Chung, Sayan Saha Roy, Amit Ghosh, Sriram Chandrasekaran.

  Single-cell optimization objective and trade-off inference (SCOOTI) is a computational framework that integrates bulk and single-cell omics data with genome-scale metabolic modeling to infer metabolic objectives and trade-offs in biological systems. Here, we present a protocol for installing and running SCOOTI, using transcriptomics, proteomics, and metabolomics data to constrain metabolic models. We describe steps to interpret metabolic priorities across different cell states or conditions through clustering, dimensionality reduction, and trade-off analysis.

Keywords:  Bioinformatics; Metabolism; Systems biology

DOI:  https://doi.org/10.1016/j.xpro.2026.104373