bims-cesirm 2026-02-15 papers

bims-cesirm

Biomed News

on Cell Signaling mediated regulation of metabolism

Issue of 2026–02–15
33 papers selected by
Tigist Tamir, University of North Carolina

Novel high-resolution ion mobility mass spectrometry for site-specific quantification of the sirtuin-5 regulated kidney succinylome.
Structural and molecular basis for allosteric regulation and catalytic coupling of human phosphoribosylformylglycinamidine synthase.
Ectopic FGFR1 Increases Intracellular Pool of Cholesterol in Prostate Cancer Cells.
AADAT-Driven Metabolic Control of Malate and CoQ 10 Shapes Immune Evasion in Triple-Negative Breast Cancer.
A Proteomic Study of the Dual Oncogenic and Tumor-Suppressive Roles of SIRT3 in Lung and Breast Cancer Cell Lines.
Deep profiling reveals coordinated remodeling of ganglioside metabolism in MCF-7 breast cancer cell line.
PTMOverlay: A Proteomic Tool to Visualize Post-Translational Modifications Across Evolution.
Metabolic permissiveness: how tissue context shapes cancer.
SOX8/CPT2 axis regulates lipid metabolism to support enzalutamide resistance in prostate cancer.
The yeast peroxisomal proteome at absolute quantitative scale.
Conformational Remodeling Underlies Activity Loss in Disease-Linked Asparagine Synthetase Variant.
The Glutamine-α-Ketoglutarate Metabolic Axis Controls Vascular Smooth Muscle Cell Function.
Myokine SIRPα exacerbates kidney disease in diabetes.
Glutamine supports human cytomegalovirus induced lipidome remodeling through reductive carboxylation.
Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.
Comprehensive Proteomics and β-Hydroxybutyrylation Profiling in Starvation-Induced Gastrocnemius Muscle Remodeling.
Spatial Multi-omics Analyses Reveal Diabetes Promotes Pancreatic Cancer Progression by Stimulating Cholesterol-Induced Neutrophil Extracellular Trap Formation.
Distinct effects of ketogenic and non-ketogenic weight-loss diets on hepatic steatosis and mitochondrial metabolism in MASLD.
Metabolic Reprogramming and Ferroptosis: Unlocking New Therapeutic Frontiers in Cancer and Diabetes.
Single-Mitochondrion ATP Profiling Directs Discovery of Targetable OXPHOS Dependency in Cancers.
CD36 enhances sensitivity of triple negative breast cancer cells to palmitate-induced ferroptosis.
Mining lysine post-translational modification sites by integrating protein language model representations with structural context.
A biological-systems-based analysis using proteomic and metabolic network inference reveals mechanistic insights into hepatic steatosis.
PEGN-PSP:Prediction of General Protein Phosphorylation Sites Using Protein Embeddings and Graph Neural Network.
The aging mouse lipidome.
IDH-mutant inhibitors enhance the sensitivity of IDH1-mutant gliomas to cysteine-methionine deprivation and ferroptosis.
Tumor-Intrinsic PD-1 Regulatory Network Drives Lapatinib Resistance in HER2⁺ Breast Cancer: An Integrative Bioinformatics Analysis.
Reconstruction of arginine deiminase pathway sustains a higher-energy state in mammalian cells.
Stress-Inducible Transcription Factor NUPR1 Is Involved in the Inhibitory Effects Exerted by Statins on Insulin Action in ER-Positive Breast Cancer Cells.
Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.
An Investigation into the Differentiation of Lactyllysine and Carboxyethyllysine Peptide Modifications by Liquid Chromatography/Mass Spectrometry.
Peroxisomes in Aging: Guardians of Cellular Resilience and Function.
FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response.

J Proteomics. 2026 Feb 11. pii: S1874-3919(26)00028-X. [Epub ahead of print] 105625

Novel high-resolution ion mobility mass spectrometry for site-specific quantification of the sirtuin-5 regulated kidney succinylome.

Birgit Schilling, Leonard Rorrer, Lauren Royer, Anne Silva-Barbosa, Katherine Pfister, Eric Goetzman, Sunder Sims-Lucas, Daniel DeBord, Joanna Bons.

  Protein post-translational modifications (PTMs) dynamically regulate essential biological and cellular processes. Lysine succinylation changes the amino acid charge, potentially affecting protein structures and functions, and dysregulation of protein succinylation may lead to metabolic disorders. Proteome-wide succinylation quantification using proteomic tools remains challenging, especially due to the low abundance of succinylated peptides and the frequent presence of isomeric PTM forms. Ion mobility spectrometry workflows that can differentiate peptidoforms with different PTM distributions represent a powerful strategy to alleviate these challenges. Recently, a new Parallel Accumulation with Mobility Aligned Fragmentation (PAMAF™) operating mode for high-resolution ion mobility-mass spectrometry (HRIM-MS) analysis based on the structures for lossless ion manipulation (SLIM) technology was introduced. Here, we first assessed the performance of PAMAF mode for protein succinylation analysis using synthetic succinylated peptides, demonstrating residue-level differentiation of co-eluting isomers and isobars and precise PTM site localization. We leveraged this novel approach to investigate succinylome remodeling in kidney tissues from wild-type and Sirtuin-5 (Sirt5) knock-out mice, a NAD+-dependent lysine de-succinylase. PAMAF acquisitions yielded ~1000 confidently identified and accurately quantified succinylated peptides and sites from mouse kidney. Sirt5 regulated succinylation of mitochondrial proteins involved in metabolic processes, including fatty acid oxidation, the tricarboxylic acid cycle, and propionate metabolism. SIGNIFICANCE: Understanding the dynamic remodeling of the protein post-translational modification landscape is critical to gain insights into the underlying molecular mechanisms of biological systems. Lysine succinylation is a recently discovered reversible post-translational modification (PTM), that regulates various biological processes and associates with diverse diseases. However, this PTM is poorly characterized, partly due to analytical barriers. Here, we present a novel mass spectrometry (MS) methodology leveraging high-resolution ion mobility (HRIM) spectrometry and Parallel Accumulation with Mobility Aided Fragmentation (PAMAF) technology to profile and quantify succinylated peptides. The unique combination of liquid chromatography, ion mobility in a very long ion path (13 m), and alternate acquisition of MS and MS/MS spectra for all ions entering the mass spectrometer provided comprehensive profiling and accurate quantification of succinylated peptides in complex matrices. This technology enabled confident resolution of succinylated isomeric peptides, that could not be differentiated without high-resolution ion mobility separation and subsequent MS/MS PTM site identification. We investigated the kidney succinylome of Sirtuin-5 (desuccinylase) knockout mice compared to wild-type mice, with over 1000 succinylated peptides identified and quantified. We analyzed the hypersuccinylation of proteins upon Sirtuin-5 deletion, especially of mitochondrial proteins involved in diverse metabolic processes.

Keywords:  High-resolution ion mobility-mass spectrometry; PTM site localization; Parallel accumulation with mobility aligned fragmentation; Post-translational modifications; Sirtuin 5; Succinylation

DOI:  https://doi.org/10.1016/j.jprot.2026.105625
Nat Commun. 2026 Feb 13.

Structural and molecular basis for allosteric regulation and catalytic coupling of human phosphoribosylformylglycinamidine synthase.

Nandini Sharma, Weijie Zhou, Jarrod B French.

Purine nucleotides are ubiquitous molecules essential for all life. The de novo biosynthesis of purines is a metabolic dependency that is frequently reprogrammed in cancers and is a well-established target for chemotherapies, immune modulation and antivirals. Here, we report cryo-electron microscopy structures of the multi-domain human phosphoribosylformylglycinamidine synthase, a central purine biosynthetic enzyme and foundational feature of the purinosome metabolon. These data capture, the proposed iminophosphate intermediate and provide the structural elucidation of an ammonia channel connecting the active sites of the glutaminase and synthase domains. Analysis of this series of structures and the accompanying biochemical data also reveal the molecular features and transient conformational changes that underlie allosteric regulation and catalytic coupling of the domains. This data resolves several longstanding mechanistic questions about this enzyme class and provides a strong foundation for therapeutic development.

DOI: https://doi.org/10.1038/s41467-026-69423-y
Int J Mol Sci. 2026 Jan 24. pii: 1190. [Epub ahead of print]27(3):

Ectopic FGFR1 Increases Intracellular Pool of Cholesterol in Prostate Cancer Cells.

Ziying Liu, Yuepeng Ke, Tingting Hong, Kennedy Smith, Peter Davies, Yun Huang, Dekai Zhang, Sanjukta Chakraborty, Yubin Zhou, Fen Wang.

  Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. However, most PCa will progress to castration-resistant PCa (CRPC) that resists ADT 1 to 3 years after the treatment. Steroidogenesis from cholesterol is one of the mechanisms leading to ADT resistance. In PCa cells, low-density lipoprotein (LDL) mediated uptake is the major venue to acquire cholesterol. However, the mechanism of regulating this process is not fully understood. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that is ectopically expressed in PCa cells and promotes PCa progression by activating downstream signaling pathways. To comprehensively determine the roles of FGFR1 in PCa, we generated FGFR1-null DU145 cells and compared the transcriptomes of FGFR1-null and wild-type cells. We found that ablation of FGFR1 reduced the expression of genes promoting LDL uptake and de novo synthesis of cholesterol, thereby reducing the overall cholesterol pool in PCa cells. Detailed mechanistic studies further revealed that FGFR1 boosted the activation of sterol regulatory element-binding protein 2 (SREBP2) through ERK-dependent phosphorylation and cleavage, which, in turn, increased the expression of low-density lipoprotein receptor (LDLR) and enzymes involved in de novo cholesterol synthesis. Furthermore, in silico analyses demonstrated that high expression of FGFR1 was associated with high LDLR expression and clinicopathological features in PCa. Collectively, our data unveiled a previously unrecognized therapeutic avenue for CRPC by targeting FGFR1-driven cholesterol uptake and de novo synthesis.

Keywords:  cholesterol; fibroblast growth factor; low-density lipoprotein; prostate cancer; sterol regulatory element-binding protein 2

DOI:  https://doi.org/10.3390/ijms27031190
bioRxiv. 2026 Jan 30. pii: 2026.01.28.702389. [Epub ahead of print]

AADAT-Driven Metabolic Control of Malate and CoQ 10 Shapes Immune Evasion in Triple-Negative Breast Cancer.

Megha Chatterjee, Franklin Gu, Susmita Samanta, Uttam Rasaily, Sai Manohar Thota, Dana Varghese, Yunping Qiu, Lynette Ewura Esi Fordwuo, Hugo Villanueva, Mary Kathryn McKenna, Jun Hyoung Park, Weijie Zhang, Lin Tian, Liqun Yu, Badrajee Piyarathna, Yang Gao, Brian Wesley Simons, Sung Yun Jung, Balasubramanyam Karanam, Vasanta Putluri, Nagi Chandandeep, Nada Mohamed, Jaya Ruth Asirvatham, Deborah Jebakumar, Arundati Rao, Carolina Gutierrez, Angela R Omilian, Carl Morrison, Gokul M Das, Christine Ambrosone, Erin H Seeley, Benny Abraham Kaipparettu, Irwin J Kurland, Nagireddy Putluri, Ahmed Elkhanany, Andrew A Davis, Qian Zhu, Xiang H-F Zhang, Arun Sreekumar.

Compared to other subtypes of breast cancer, triple-negative breast cancers (TNBC) have fewer treatment options and exhibit a worse prognosis. Through integrated transcriptomic, metabolomic, immunohistochemical, spatial, and clinical analyses, we identify the mitochondrial enzyme, α-aminoadipate aminotransferase (AADAT) as a previously unrecognized metabolic immune checkpoint in TNBC. AADAT mRNA and protein were significantly upregulated in human TNBC, and high AADAT expression was associated with reduced intra-tumoral CD8⁺ T-cell density and inferior survival. Genetic silencing of AADAT in orthotopic murine TNBC models curtailed primary tumor growth and distant metastasis in a CD8⁺ T-cell-dependent manner, enhanced effector T-cell activation, and sensitized tumors to dual PD-1/CTLA-4 blockade. Mechanistically, unbiased metabolomics showed increased malate levels after AADAT knockdown. Additionally, 4-hydroxyphenylpyruvate, an essential precursor for coenzyme Q 10 (CoQ 10 ) biosynthesis, decreased following AADAT knockdown, suggesting an impaired mitochondrial electron transport chain. CoQ 10 supplementation restored metabolic balance and reversed malate accumulation caused by AADAT knockdown, indicating that AADAT helps maintain CoQ 10 -supported redox homeostasis, thereby preventing malate buildup and export. Notably, malate addition directly boosted CD8⁺ T-cell oxidative metabolism, increased the NAD⁺/NADH ratio and reactive oxygen species, and augmented TNF-α and IFN-γ production. In vivo, malate supplementation in drinking water phenocopied AADAT knockdown, restored the response to paclitaxel plus anti-PD-1 therapy in multiple independent syngeneic TNBC models with de novo or acquired resistance to immunotherapy, reduced tumor burden, and prolonged survival. In patient cohorts, higher spatially clustered intra-tumoral malate is associated with co-localization of functional CD8⁺ T cells, decreased exhausted T-cell neighborhoods, and superior post-chemotherapy outcomes. These data position AADAT as a central metabolic orchestrator of immune escape in TNBC and nominate oral malate as a readily translatable adjuvant to reverse chemo-immunotherapy resistance in TNBC.
Statement of Significance: AADAT defines a metabolic-immune axis driving immune evasion and therapy resistance in triple-negative breast cancer. Blocking AADAT or administering oral malate reactivates CD8⁺ T-cell immunity and sensitizes chemo-immunotherapy-resistant tumors to these agents. These findings uncover a readily translatable metabolic vulnerability with potential to improve outcomes for patients with aggressive breast cancer subtypes.

DOI: https://doi.org/10.64898/2026.01.28.702389
Int J Mol Sci. 2026 Jan 28. pii: 1325. [Epub ahead of print]27(3):

A Proteomic Study of the Dual Oncogenic and Tumor-Suppressive Roles of SIRT3 in Lung and Breast Cancer Cell Lines.

Marisol Ayala Reyes, Diana Lashidua Fernández Coto, Ramiro Alonso Bastida, György Marko-Varga, Jeovanis Gil, Sergio Encarnación-Guevara.

  Mitochondria play a crucial role in metabolism and energy production by generating adenosine triphosphate (ATP) through oxidative phosphorylation. They also help maintain intracellular calcium levels, facilitate communication between the nucleus and cytoplasm, detoxify reactive oxygen species (ROS), and regulate apoptosis. Reversible acetylation of mitochondrial proteins is a key post-translational modification influencing these processes, with the NAD+-dependent deacetylase SIRT3 being a major regulator. While SIRT3 has been described as a tumor suppressor in some contexts and as a tumor promoter in others, its role appears to be tissue- and metabolism-specific. Here, we compared the proteomic and acetylomic responses of lung adenocarcinoma (A549) and breast adenocarcinoma (MCF7) cell lines to SIRT3 inhibition by 3-TYP. The two lines were selected based on distinct metabolic phenotypes and reported differences in basal SIRT3 abundance. Total proteome and mitochondrial-enriched fractions were analyzed separately for each cell line to avoid cross-line normalization bias. We identified 6457 proteins and 4199 acetylated peptides, revealing distinct pathway enrichments and acetylation changes after SIRT3 inhibition. A549 cells showed increased oxidative metabolism, while MCF7 cells exhibited metabolic reprogramming. These results indicate that the proteomic impact of SIRT3 modulation is strongly influenced by cellular metabolic context. All raw mass spectrometry data are publicly available in PXD063181.

Keywords:  acetylation; cancer; metabolism; mitochondria; oxidative phosphorylation; post-translational modification; sirtuin

DOI:  https://doi.org/10.3390/ijms27031325
Chem Sci. 2026 Jan 26.

Deep profiling reveals coordinated remodeling of ganglioside metabolism in MCF-7 breast cancer cell line.

Yichun Wang, Gaoge Sun, Hang Yin, Yu Xia.

Gangliosides are vital cell membrane components whose metabolic dysregulation is implicated in various cancers. However, a systems-level understanding of their metabolism has been hindered by their structural complexity and low cellular abundance. Herein, we have developed a deep profiling workflow for gangliosides that integrates selective enrichment, liquid chromatography-ion mobility spectrometry, and isomer-resolved tandem mass spectrometry. This workflow enhances detection sensitivity 100-fold, enabling the identification of 391 ganglioside structures in a human breast adenocarcinoma cell line (MCF-7) at multiple structural levels. We further reveal coordinated remodeling of gangliosides in MCF-7 cancer cells, including shifts toward a-series glycans, increased incorporation of long-chain sphingosine bases, and altered C[double bond, length as m-dash]C location isomers. By integrating these lipidomic findings with targeted gene expression analysis and quantitative proteomics, we reconstruct a ganglioside biosynthetic network that delineates dysregulation across five key structural modules. This lipid-centric approach offers new insights into the metabolic reprogramming of gangliosides and holds potential for studying lipid metabolism in diverse diseases.

DOI: https://doi.org/10.1039/d5sc09445c
bioRxiv. 2026 Feb 06. pii: 2026.02.03.703592. [Epub ahead of print]

PTMOverlay: A Proteomic Tool to Visualize Post-Translational Modifications Across Evolution.

Camille Krieger, Zachary Everton, Youngki You, Brandon Lewis, Thomas Bank, Meagan C Burnet, Sarai Williams, Hanna E Walukiewicz, Christopher V Rao, Alan J Wolfe, Samuel H Payne, Ernesto S Nakayasu.

Evolutionary conservation has been considered a hallmark of essential basic functions in cells. Therefore, the study of evolutionarily conserved post-translational modifications (PTMs) can provide insight into their role in protein function. In this context, mass spectrometry can identify and quantify thousands of PTM sites. However, a major bottleneck lies in analyzing the large amounts of data collected by the mass spectrometer. Here we address the need for a protein sequence alignment tool for multiple PTMs across several species. We developed a tool named PTMOverlay that takes peptide identification output files and overlays PTM sites onto multiple protein sequence alignments. Examining 31 bacteria isolates, we combined their protein sequences with select PTM types, including acetylation, phosphorylation, monomethylation, dimethylation, and trimethylation. The tool revealed a variety of conserved modification sites on the bacterial central carbon metabolism. Further structural analysis revealed possible interactions between methylated arginine and lysine residues with phosphothreonine/serine sites on the homodimer interface of enolase. Overall, this tool can parse large amounts of mass spectrometry data and allows for more informed and efficient selection of sites for future studies of protein function.

DOI: https://doi.org/10.64898/2026.02.03.703592
Genes Dev. 2026 Feb 09.

Metabolic permissiveness: how tissue context shapes cancer.

Chrysanthi Moschandrea, Christian Frezza.

  An emerging paradox in cancer metabolism is that identical oncogenic mutations produce profoundly different metabolic phenotypes depending on tissue context, with many mutations exhibiting striking tissue-restricted distributions. Here we introduce metabolic permissiveness as the inherent capacity of a tissue to tolerate, adapt to, or exploit metabolic disruptions, providing a unifying framework for explaining this selectivity. We examine tissue-specific metabolic rewiring driven by canonical oncogenes (MYC and KRAS), tumor suppressors (p53, PTEN, and LKB1), and tricarboxylic acid (TCA) cycle enzymes (FH, SDH, and IDH), demonstrating that baseline metabolic architecture, nutrient microenvironment, redox buffering, and compensatory pathways determine whether mutations confer a selective advantage or metabolic crisis. We further discuss how the tumor microenvironment shapes metabolic adaptation and therapeutic vulnerability. This framework reveals shared principles of tissue-specific metabolic vulnerability in cancer and provides a mechanistic basis for precision metabolic therapies.

Keywords:  cancer; metabolism; permissiveness

DOI:  https://doi.org/10.1101/gad.353516.125
Cancer Cell Int. 2026 Feb 10.

SOX8/CPT2 axis regulates lipid metabolism to support enzalutamide resistance in prostate cancer.

Songsong Liu, Dingyong Zhang, Chao Jiang, Xin Chen, Liang Jin, Shiyong Xin, Xianchao Sun.

   BACKGROUND: Although androgen receptor (AR)-targeted therapies have shown notable clinical efficacy in prostate cancer (PCa), the emergence of drug resistance remains a critical factor driving the clinical prognosis in castration-resistant prostate cancer (CRPC). Aberrant tumor lipid metabolism not only fulfills the energetic and biosynthetic requirements of rapidly proliferating cancer cells but also contributes to the development of therapeutic resistance.
METHODS: We examined SOX8 expression in enzalutamide resistance (EnzR) cell lines and validated its association with tumor progression and clinical outcome. The malignant phenotypes related to EnzR were assessed in vitro using PCa cell lines with stable SOX8 overexpression or knockdown. Tumor xenografts were subsequently generated by inoculating the corresponding cell lines into nude mice. To elucidate the underlying mechanisms, we conducted RNA-seq, CUT&Tag, non-targeted metabolomics, and a series of molecular and biochemical assays.
RESULTS: SOX8 expression was elevated in EnzR prostate cancer cell lines and positively correlated with poor patient prognosis. Reduced SOX8 expression enhanced cellular sensitivity to enzalutamide, whereas elevated SOX8 expression decreased drug responsiveness. Chromatin immunoprecipitations (ChIP) assays revealed that AR was enriched at the SOX8 promoter region and transcriptionally repressed SOX8. In vivo, stable SOX8 knockdown markedly suppressed tumor growth in nude mouse xenografts. Mechanistically, SOX8 promotes the EnzR by reprograming lipid metabolism and we identified carnitine palmitoyltransferase 2 (CPT2), a key enzyme in lipid metabolism, as a novel downstream target of SOX8. SOX8-driven lipid metabolic reprogramming promoted enzalutamide resistance through the SOX8/CPT2 axis.
CONCLUSIONS: High SOX8 expression promotes EnzR in PCa, suggesting SOX8 as a potential therapeutic target. Our findings demonstrate that SOX8 drives EnzR by activating the SOX8/CPT2 axis, thereby inducing lipid metabolic reprogramming in PCa cells.

Keywords:  CPT2; Enzalutamide resistance; Lipid metabolism; Prostate cancer; SOX8

DOI:  https://doi.org/10.1186/s12935-026-04215-4
Histochem Cell Biol. 2026 Feb 13. 164(1): 8

The yeast peroxisomal proteome at absolute quantitative scale.

Hirak Das, Silke Oeljeklaus, Renate Maier, Julian Bender, Bettina Warscheid.

  Peroxisomes are dynamic organelles vital for lipid metabolism and redox homeostasis. In Saccharomyces cerevisiae, the expression of peroxisomal proteins is tightly regulated in response to metabolic conditions. Here, we provide the first absolute quantification of the yeast peroxisomal proteome under peroxisome-inducing (oleate) and fermentative (glucose) conditions using a label-free mass spectrometry approach. We determined protein copy numbers for ~ 4500 proteins, including 99 peroxisomal and peroxisome-associated proteins. Our data reveal that the overall peroxisomal proteome is approximately threefold more abundant in oleate-grown cells, constituting 2.8% (2.01 × 106 protein copies) of the total proteome compared to 0.8% (6.67 × 105 protein copies) in glucose. Considering only peroxisomal core proteins, i.e., proteins exclusively or predominantly localized in peroxisomes, total copy numbers for peroxisomal proteins were even ninefold higher on oleate (0.9%, 6.29 × 105 protein copies) compared to glucose (0.1%, 7.78 × 104 protein copies), reflecting the necessity for peroxisomal functions such as fatty acid beta-oxidation. Enzymes of the beta-oxidation and glyoxylate cycle showed up to > 500-fold higher abundance in oleate. In contrast, core components of the peroxisomal protein import machinery (e.g., Pex5, Pex14) exhibited only moderate changes (~ 2- to 8-fold). In addition to metabolic enzymes and components of the peroxisomal protein import pathways, we provide copy number data for proteins involved in cellular stress response, peroxisome proliferation, division and organization, peroxisome-associated membrane contact sites, and metabolite transporter. Taken together, our dataset offers a quantitative framework of peroxisomal remodeling under different metabolic conditions and highlights the organelle's adaptive flexibility, providing a valuable resource for future studies on peroxisome biology.

Keywords:   Saccharomyces cerevisiae ; Absolute quantification; Mass spectrometry; Peroxisomes; Protein copy numbers; Proteomic ruler

DOI:  https://doi.org/10.1007/s00418-026-02458-w
bioRxiv. 2026 Feb 03. pii: 2026.02.01.703106. [Epub ahead of print]

Conformational Remodeling Underlies Activity Loss in Disease-Linked Asparagine Synthetase Variant.

Lucciano A Pearce, Adriana Coricello, Alanya J Nardone, Giovanni Bottegoni, Yuichiro Takagi, Wen Zhu.

Asparagine synthetase deficiency (ASNSD) is a devastating congenital disorder characterized by profound neurological impairment and early childhood mortality. It is associated with pathogenic mutations in the asparagine synthetase (ASNS) gene. Despite the critical role of ASNS in the amino acid cycle, the molecular basis by which ASNSD-linked missense mutations impair enzyme function remains poorly understood. Here, we present a comprehensive characterization of a recurrent ASNSD-linked variant, R48Q. Steady-state kinetic assays reveal severe reductions in L-glutamine-dependent catalysis and disrupted product stoichiometry, implicating impaired interdomain communication. Cryogenic electron microscopy (cryo-EM) and 3D variable analysis of the EM map uncovers altered loop conformations at the N-terminal active site and subtle conformational changes at the C-terminal domain. Consistent with the structural data, molecular dynamics simulations support that the local disruption propagates across the protein, thereby decoupling coordinated domain motions essential for catalysis. Additionally, we demonstrate that the flanking arginine and the affected loop are evolutionarily conserved across Class II glutamine amidotransferases, highlighting their shared mechanistic importance. These findings provide the molecular basis of an ASNSD variant and establish a framework for understanding how point mutations disrupt complex enzyme dynamics, with broad implications for precision medicine.
Significance: Understanding how mutations affect multidomain enzymes is crucial for elucidating the molecular mechanisms underlying genetic disorders. Here, we examine the molecular consequences of the R48Q variant in human asparagine synthetase (ASNS), the sole enzyme responsible for de novo L-asparagine synthesis; mutations of this enzyme lead to a fatal neurometabolic disorder, asparagine synthetase deficiency (ASNSD). By combining biochemical, cryogenic electron microscopy, and molecular dynamics simulation, we show that a single N-terminal amino acid substitution disrupts both local and global coordination, impairing enzyme activity. Our work provides the first mechanistic blueprint of an ASNSD-linked variant. These findings not only deepen our understanding of ASNS but also offer a generalized framework for studying the dynamic regulation of multidomain enzymes in disease.

DOI: https://doi.org/10.64898/2026.02.01.703106
Cells. 2026 Jan 26. pii: 230. [Epub ahead of print]15(3):

The Glutamine-α-Ketoglutarate Metabolic Axis Controls Vascular Smooth Muscle Cell Function.

Kelly J Peyton, Xiao-Ming Liu, Giovanna L Durante, William Durante.

  Glutamine is a known regulator of vascular smooth muscle cell (VSMC) function, but the molecular pathways underlying this response remain incompletely understood. This study investigated how glutamine metabolism influences VSMC behavior and identified the responsible enzymes and metabolites. Glutamine deprivation markedly reduced VSMC proliferation, migration, and collagen synthesis, while modestly decreasing viability. Pharmacological inhibition of glutaminase-1 (GLS1) or aminotransferases (AT) similarly suppressed these cellular functions, whereas inhibiting glutamate dehydrogenase 1 (GLUD1) had no effect. Metabolite analysis revealed that glutamine deprivation or AT inhibition, but not GLUD1 inhibition, reduced intracellular α-ketoglutarate (αKG) concentrations, establishing AT as the primary enzyme converting glutamine-derived glutamate to αKG. To identify which metabolite drives VSMC responses, glutamine-starved cells were supplemented with various glutamine-derived molecules. The cell-permeable αKG analog dimethyl-αKG significantly restored VSMC proliferation, migration, collagen synthesis, and survival, while ammonia only enhanced viability, demonstrating αKG's primary role in mediating glutamine-dependent functions. These findings establish that glutamine metabolism via the GLS1-AT-αKG pathway is a critical driver of VSMC activation and survival. Targeting this glutamine-αKG metabolic axis through GLS1 inhibition, AT blockade, or downstream αKG disruption offers a compelling therapeutic strategy for ameliorating fibroproliferative vascular diseases, including atherosclerosis, post-angioplasty restenosis, and pulmonary hypertension.

Keywords:  aminotransferase; collagen; glutaminase; glutamine; migration; proliferation; vascular smooth muscle cells; viability; α-ketoglutarate

DOI:  https://doi.org/10.3390/cells15030230
JCI Insight. 2026 Feb 09. pii: e183392. [Epub ahead of print]11(3):

Myokine SIRPα exacerbates kidney disease in diabetes.

Jiao Wu, Elisa Russo, Daniela Verzola, Qingtian Li, Helena Zhang, Bhuvaneswari Krishnan, David Sheikh-Hamad, Zhaoyong Hu, William E Mitch, Sandhya S Thomas.

  Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced intramuscular fat deposition when compared with flox mice on HFD. Moreover, mSIRPα-KO mice displayed enhanced kidney tubular fatty acid oxidation (FAO) expression with suppressed intraorgan triglycerides deposition, and importantly, protection against DKD. Conversely, exogenous SIRPα impaired kidney proximal tubular cell FAO, ATP production, and exacerbated fibrosis. Finally, suppressing SIRPα in skeletal muscles or treatment with anti-SIRPα monoclonal antibodies in STZ-treated mice mitigated cachexia, hyperlipidemia, kidney triglyceride deposition, and renal dysfunction in spite of significant hyperglycemia. Importantly, serum SIRPα was upregulated in patients with DKD. In conclusion, SIRPα serves as a potential biomarker and therapeutic target in DKD.

Keywords:  Chronic kidney disease; Diabetes; Endocrinology; Nephrology

DOI:  https://doi.org/10.1172/jci.insight.183392
bioRxiv. 2026 Jan 27. pii: 2026.01.26.701865. [Epub ahead of print]

Glutamine supports human cytomegalovirus induced lipidome remodeling through reductive carboxylation.

Rebekah L Mokry, Caleb B de Lacy, John G Purdy.

Lipidome remodeling during human cytomegalovirus (HCMV) replication is a complex process that requires induction of lipogenic proteins and altered metabolite flow to support synthesis of fatty acids and lipids. HCMV infection increases the utilization of glucose and acetate to provide enough carbons to support increased demand for lipogenesis during virus replication, but other carbon contributors have not been studied. Here, we identify glutamine as a carbon source for lipogenesis during HCMV infection. Metabolic tracing with 13 C-labeled glutamine revealed carbons from glutamine are enriched in phospholipids and neutral lipids during infection, including phosphatidylcholine, phosphatidylethanolamine, diacylglycerol, and triacylglycerol. Additional metabolic tracing demonstrates that HCMV infection promotes glutamine flow to fatty acid synthesis primarily through reductive carboxylation, i.e., conversion of glutamine to citrate through isocitrate. Through the use of two different 13 C-labeled forms of glutamine, we found that ∼30% of the carbons from glutamine are delivered to fatty acid synthesis through additional metabolic means. Our current understanding of metabolite utilization during HCMV replication is based on cell culture models where there is an excess amount of glucose, suggesting that deriving carbons from glutamine might be needed when glucose levels are low. To determine if concentrations of glucose and glutamine change their contributions to fatty acid synthesis, we investigated lipogenesis when glucose and glutamine are at physiological levels (5 mM and 0.55 mM, respectively). We determined that physiological levels of glucose and glutamine are sufficient to support the increased demand for fatty acid synthesis caused by HCMV infection, despite a reduction in virus production. Using metabolic tracing with 13 C-labeled forms of glucose or glutamine, we determined that both carbon sources still contribute to fatty acid synthesis when present at physiological levels. Overall, our results identify viral activation of reductive carboxylation that increases glutamine flow to lipogenesis during infection. This work provides additional insight into metabolic reprogramming that supports HCMV-induced lipidome remodeling.
Author Summary: Many viruses hijack cellular metabolic processing to obtain the components needed for replication. Human cytomegalovirus (HCMV) uses several mechanisms to reprogram lipid metabolism and remodel the lipidome of infected cells. HCMV promotes synthesis of very long chain fatty acids that are found in phospholipids and triacylglycerol. Glucose and acetate contribute carbon to fatty acid synthesis and elongation following HCMV infection. In this work, we demonstrate that glutamine is an additional carbon source for fatty acid and lipid synthesis. Phospholipids and neutral lipids are enriched with carbons from glutamine during HCMV infection. Mechanistically, HCMV induces reductive carboxylation to increase glutamine flow to fatty acid synthesis and increased metabolite availability supports additional carbon flow to fatty acids. Overall, this study provides additional insight into virus-induced metabolic remodeling that supplies the molecular building blocks for virus replication.

DOI: https://doi.org/10.64898/2026.01.26.701865
Nat Commun. 2026 Feb 12. 17(1): 1493

Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.

Sathish Babu Vasamsetti, Samreen Sadaf, Mohammad A Uddin, Jixing Shen, Ebin Johny, Awishi Mondal, Jonathan Florentin, Liqun Lei, Aleef Mannan, Krithika Sudhakar Rao, John Sembrat, Mauricio Rojas, Ian Sipula, Jake Kastroll, Michael J Jurczak, Sruti Shiva, Robert M O'Doherty, Vijay Yechoor, Partha Dutta.

How cellular metabolism facilitates tissue-resident macrophage maintenance remains elusive. Here we show that visceral adipose tissue (VAT)-resident macrophages, unlike monocyte-derived macrophages, are enriched with mitochondrial-specific antioxidant enzymes restraining inflammation and promoting VAT homeostasis and insulin sensitivity. Additionally, VAT resident macrophages express high levels of plasminogen activator inhibitor type 2, encoded by SerpinB2, which is involved in the blood coagulation cascade. SerpinB2 promotes adipose resident macrophage survival by regulating mitochondrial oxidative phosphorylation and preventing the release of pro-apoptotic cytochrome c from the mitochondria into the cytoplasm via antioxidant glutathione production. Chronic inflammation, such as obesity, diminishes SerpinB2 expression in VAT macrophages in patients and mice, leading to the decline of this macrophage subset. Mechanistically, interferon-γ elevation in diabetes induces Ikaros, a transcriptional suppressor, which binds to the SerpinB2 promoter and decreases SerpinB2 expression. Congruently, selective depletion of the IFN-γ receptor in myeloid cells or supplementation of macrophage-specific SerpinB2 deficient mice with N-acetylcysteine, a glutathione precursor, restores VAT resident macrophage survival, decreases adipocyte size, and improves glucose tolerance and insulin sensitivity. Our data thus reveal an unexpected function of SerpinB2 in the regulation of mitochondrial function and survival of tissue-resident macrophages.

DOI: https://doi.org/10.1038/s41467-026-69196-4
Biology (Basel). 2026 Feb 06. pii: 289. [Epub ahead of print]15(3):

Comprehensive Proteomics and β-Hydroxybutyrylation Profiling in Starvation-Induced Gastrocnemius Muscle Remodeling.

Leilei Cui, Chunping Huang, Yu Su, Shiqi Xu, Liang Zha, Qiuyuan Zhao, Wu Quan, Xinqiang Lan, Yang Xiang, Qiquan Wang.

  Starvation elicits profound metabolic adaptations in skeletal muscle, enabling survival during nutrient scarcity. While global proteomic changes underpinning muscle atrophy have been studied, the role of lysine β-hydroxybutyrylation (Kbhb), a novel metabolite-derived post-translational modification linked to ketone metabolism, remains largely unexplored. In this study, we subjected mice to 72 h of food deprivation and performed integrative quantitative proteomics and Kbhb-modified peptide profiling on gastrocnemius muscle. Starvation induced significant body weight and muscle mass loss, accompanied by increased systemic β-hydroxybutyrate levels and widespread Kbhb modification of muscle proteins. Proteomic analysis revealed extensive downregulation of ribosomal and translation-associated proteins, coupled with upregulation of autophagy and lipid catabolism pathways, highlighting a coordinated shift from anabolic processes to catabolic and oxidative metabolism. Deep Kbhb profiling identified over 7500 modified lysine sites across 2000 proteins, with starvation triggering a global increase in Kbhb on key metabolic enzymes involved in glycolysis, TCA cycle, fatty acid β-oxidation, and amino acid metabolism. Notably, starvation-enhanced Kbhb preferentially targeted evolutionarily conserved lysines proximal to catalytic or cofactor-binding domains, implicating a regulatory role in enzymatic activity modulation. Conversely, Kbhb on structural and contractile proteins was downregulated, suggesting functional reprioritization of muscle physiology during fasting. Our findings uncover lysine β-hydroxybutyrylation as a dynamic, metabolically responsive PTM mediating gastrocnemius muscle adaptation to energy deficiency, expanding the paradigm of potentially metabolite-driven epigenetic and non-epigenetic regulatory mechanisms in muscle metabolism.

Keywords:  ketone body; lysine β-hydroxybutyrylation (Kbhb); proteomics; skeletal muscle; starvation

DOI:  https://doi.org/10.3390/biology15030289
Cancer Res. 2026 Feb 09.

Spatial Multi-omics Analyses Reveal Diabetes Promotes Pancreatic Cancer Progression by Stimulating Cholesterol-Induced Neutrophil Extracellular Trap Formation.

Guanqun Li, Can Zhang, Tianqi Lu, Ziwei Zhang, Jiafu Wu, Rui Bai, Yan Luo, Fengyi Wang, Yiqin Song, Liwei Liu, Jisheng Hu, Yongwei Wang, Gang Wang, Hongtao Tan, Hua Chen, Rui Kong, Le Li, Bei Sun.

Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) exhibit poor clinical outcomes. Metabolic reprogramming of both cancer cells and immune compartments plays a crucial role in shaping the anti-tumor immune response in PDAC. DM-induced metabolic alteration may disrupt the intricate crosstalk between immune cells and tumor-associated immune factors, profoundly influencing PDAC progression. Here, we performed an integrated, spatially resolved multi-omics study to investigate DM-associated, cell-speciﬁc metabolic remodeling within the PDAC tumor microenvironment. DM influenced interactions between tumor cells and immune cells, which accelerated PDAC growth in both humans and mice. PDAC patients with DM exhibited higher tumor-stage, poorer differentiation, and worse outcomes. Spatial metabolic and transcriptional profiling revealed that SREBP2-dependent cholesterol biosynthesis exacerbated PDAC progression. Increased cholesterol biosynthesis promoted neutrophil recruitment and accelerated formation of neutrophil extracellular traps (NETs) by stimulating the CXCL1-CXCR1/CXCR2 signaling axis, ultimately promoting PDAC growth. Inhibition of SREBP2, pharmacological blockade of CXCL1, or perturbation of NETs markedly reduced PDAC growth in diabetic mouse models. Together, these multi-omics analyses and follow-up mechanistic studies constitute an integrated approach that elucidates a metabolic mechanism by which diabetes promotes PDAC development by remodeling the tumor immune microenvironment and highlights a potential therapeutic strategy for PDAC with DM.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2854
J Hepatol. 2026 Feb 06. pii: S0168-8278(26)00062-0. [Epub ahead of print]

Distinct effects of ketogenic and non-ketogenic weight-loss diets on hepatic steatosis and mitochondrial metabolism in MASLD.

Sami F Qadri, Kimmo Porthan, Sylvie Dufour, Tiina E Lehtimäki, Kitt Falk Petersen, Gerald I Shulman, Hannele Yki-Järvinen, Panu K Luukkonen.

   BACKGROUND & AIMS: Weight loss is the cornerstone therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal dietary approach for reducing intrahepatic triglycerides (IHTG) and the mechanisms underlying steatosis resolution remain poorly defined. We investigated whether weight loss via a ketogenic diet (KD) differentially affects IHTG content, hepatic mitochondrial metabolism, and the circulating metabolome compared with a non-ketogenic diet (ND).
METHODS: Individuals with varying IHTG content underwent short-term hypocaloric KD and ND in a crossover design. Before and after each diet, IHTG was quantified by proton magnetic resonance spectroscopy and liver stiffness by magnetic resonance elastography. We used state-of-the-art isotope tracer methodology to compare KD and ND effects on in vivo rates of hepatic mitochondrial tricarboxylic acid (TCA) cycle oxidation, endogenous glucose production, and β-hydroxybutyrate production (ketogenesis). Targeted plasma metabolomics by NMR and LC-MS evaluated systemic metabolic responses.
RESULTS: Despite similar energy deficits and body fat loss, IHTG decreased 45% more with KD than ND (-29% vs. -20%), accompanied by a threefold greater improvement in hepatic insulin sensitivity (59% vs. 21%). KD, but not ND, markedly reduced serum insulin concentrations (-54%), thereby promoting lipolysis and intrahepatic fatty acid partitioning toward mitochondrial β-oxidation, increasing hepatic mitochondrial [NADH]/[NAD+] (redox state) (+51%), and decreasing rates of hepatic mitochondrial TCA cycle oxidation (-34%). KD, but not ND, increased plasma concentrations of branched-chain amino acids, acylcarnitines, and tricarboxylic acid cycle intermediates.
CONCLUSIONS: Both diets ameliorated MASLD, but KD produced a greater reduction in IHTG owing to a starvation-like metabolic state. However, the benefits of KD were accompanied by increased hepatic mitochondrial redox state and suppression of TCA cycle oxidation, which are features previously linked to progressive liver injury.
IMPACT AND IMPLICATIONS: This study provides mechanistic justification for considering dietary composition, in addition to caloric restriction, as a key determinant of steatosis resolution in MASLD. The findings highlight a potential trade-off between greater short-term reductions in liver fat and the emergence of metabolic features previously associated with increased susceptibility to liver injury. While a ketogenic diet may facilitate rapid liver fat reduction in selected clinical contexts, its use should be approached cautiously, particularly in individuals with advanced MASLD. These results underscore the need for systematic evaluation of dietary composition as a determinant of both efficacy and safety of nutritional interventions for MASLD.
CLINICAL TRIAL NUMBER: NCT03737071.

Keywords:  caloric restriction; citric acid cycle; cross-over study; energy metabolism; fatty liver; humans; insulin resistance; ketogenic diet; metabolome; redox state; weight loss

DOI:  https://doi.org/10.1016/j.jhep.2026.02.001
Antioxid Redox Signal. 2026 Feb 13. 15230864261421487

Metabolic Reprogramming and Ferroptosis: Unlocking New Therapeutic Frontiers in Cancer and Diabetes.

Yan Huo, Yaoxiong Xia, Qiuyi Zhang, Yanjie Li, Yu Zhao, Zhiyong Li, Danyu Zhu, Fangpei Ma, Zhun Gu, Nannan Zhang, Yanping Gao.

   SIGNIFICANCE: Ferroptosis, an iron- and lipid peroxidation-dependent mode of programmed cell death, is presently realized as a converging mediator that bridges redox imbalance and metabolic dysfunction. Differing from apoptosis and necroptosis, ferroptosis involves iron homeostasis, glutathione depletion, and redox lipid damage. Thus, it becomes the intersection of metabolic reprogramming and redox signaling. Ferroptosis is a double-edged metabolic vulnerability and adaptive resistance pathway in malignancy.
RECENT ADVANCES: Oncogenic signaling cascades such as PI3K/Akt/mTOR and AMPK restructure glucose and lipid metabolism to regulate ferroptotic sensitivity, whereas cancer cells destabilize antioxidant defense pathways such as Xc--GSH-GPX4 and FSP1-CoQ10-NAD(P)H pathways to evade ferroptotic cell death. Pharmacological inducers erastin, RSL3, and sorafenib reverse oxidative imbalance, enhance antitumor effect, and immune modulation in the tumor microenvironment. In diabetic mellitus complications, ferroptosis is responsible for β-cell deterioration, insulin resistance, and vascular injury. Hyperglycemia-induced oxidative stress and dysregulated GPX4 facilitate lipid peroxidation and ferroptotic cell death in pancreatic β-cells, while iron overload and mitochondrial dysfunctions facilitate ferroptotic injury in diabetic cardiomyopathy, nephropathy, retinopathy, and foot ulcer. These observations position ferroptosis as a crucial metabolically reorganized hub of organ damage.
CRITICAL ISSUES: Despite rapid advancements, foundational challenges persist, including the identification of ferroptosis-specific biomarkers, tissue-specific thresholds, and mechanisms for neutralizing off-target toxicity.
FUTURE DIRECTIONS: Recently developed technologies such as CRISPR-based functional genomics, metabolomics, and AI-powered modeling represent new-age tools in defining ferroptosis networks and precision therapeutics design. Integration of the regulation of normal physiological ferroptosis into cancer and diabetes therapy has the potential to redefine redox-targeted therapy and metabolic medicine. Antioxid. Redox Signal. 00, 000-000.

Keywords:  cancer metabolism; diabetes mellitus; ferroptosis; iron metabolism; lipid peroxidation; metabolic reprogramming; redox homeostasis; therapeutic targeting; tumor microenvironment; β-cell dysfunction

DOI:  https://doi.org/10.1177/15230864261421487
Adv Sci (Weinh). 2026 Feb 13. e13341

Single-Mitochondrion ATP Profiling Directs Discovery of Targetable OXPHOS Dependency in Cancers.

Xu Xiao, Cheng Lu, Hao Chen, Jing Zhou, Yunyun Hu, Haonan Di, Guoqiang Su, Xiaomei Yan.

  Mitochondrial adenosine triphosphate (mitoATP) serves as the primary bioenergetic currency for oxidative phosphorylation (OXPHOS)-driven malignancies, yet its precise organelle-level quantification remains challenging due to mitochondrial heterogeneity and cytosolic interference. Herein, we report MitoATP-nFCM, a nano-flow cytometry platform enabling single-mitochondrion ATP measurement via simultaneous fluorescence and side scatter detection. We uncover 1.7-1.9-fold higher ATP levels in isolated mitochondria from breast (MCF-7, MDA-MB-231) and colon (HCT-15, HCT-116) cancer cells than in their normal counterparts. Single-organelle analysis further reveals coordinated metabolic reprogramming in cancer mitochondria, featuring elevated membrane potential, increased ATP synthase expression, and reduced hexokinase 2 levels, demonstrating their OXPHOS-dominant bioenergetic phenotype that contrasts with classical Warburg-effect expectations. Furthermore, we establish a screening strategy to identify highly potent cancer-selective inhibitors targeting mitochondrial metabolism. We find that bedaquiline (ATP synthase inhibitor) outperforms oligomycin A in specificity, VLX600 (electron transport chain inhibitor) shows superior selectivity to rotenone/metformin, and CPI-613 (tricarboxylic acid cycle blocker) surpasses other glutaminase inhibitors. MitoATP-nFCM establishes a quantitative single-organelle platform that profiles elevated mitoATP levels in cancer cells and enables precision screening of OXPHOS-targeting inhibitors.

Keywords:  cancer vulnerability; mitochondrial ATP; mitochondrial metabolism; precision cancer therapy; single‐organelle analysis

DOI:  https://doi.org/10.1002/advs.202513341
Cell Death Dis. 2026 Feb 11.

CD36 enhances sensitivity of triple negative breast cancer cells to palmitate-induced ferroptosis.

Lara Closset, Jean-Philippe Foy, Lila Louadj, Elodie Pramil, Elisabetta Marangoni, Ivan Bieche, Michèle Sabbah.

Ferroptosis is a newly identified programmed cell death induced by iron-driven lipid peroxidation and implicated as a potential approach for tumor treatment. Breast tumors develop in a complex microenvironment whose main component is adipose tissue and gain aggressiveness through increased fatty acid uptake. Here, we demonstrated that palmitic acid (PA) induced ferroptosis in triple negative breast cancers (TNBC). We found that PA increases the protein expression levels of the long-chain fatty acid transporter CD36, leading to increased lipid uptake. Mechanistically, overexpression of CD36 increases lipid peroxidation, mitochondrial ROS production, the labile iron pool, and especially Fe2+ content. Additionally, we found increased expression of ferroptotic target genes (HMOX1, ACSL1, SAT1) and decreased of anti-ferroptotic genes (GPX4 and FSP1) in TNBC following PA exposure. Overexpression of CD36 did not induce ferroptosis in estrogen receptor positive breast cancer. Clinically, higher CD36 expression correlated with the luminal androgen receptor (LAR) subtype of TNBC, known to exhibit a higher sensitivity to ferroptosis. Altogether, these data provide evidence for an essential role of the CD36 protein in the ferroptotic process induced by the saturated fatty acid PA, opening potential new therapeutic approaches promoting ferroptosis in the most aggressive breast cancers.

DOI: https://doi.org/10.1038/s41419-026-08460-3
Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2529141123

Mining lysine post-translational modification sites by integrating protein language model representations with structural context.

Mengqi Luo, Xiaohong Zhu, Chen Bai, Arieh Warshel, Luonan Chen.

  Lysine (Lys/K) residues serve as major hubs for post-translational modifications (PTMs) owing to the chemical versatility of their ε-amino groups, giving rise to diverse regulatory functions. Accurate and efficient identification of modified lysine residues therefore requires computational models that can effectively capture both sequence and structural information while minimizing domain-specific feature engineering. In this study, we propose a unified deep learning framework for lysine PTM site identification that integrates sequence representations derived from a protein language model with atom-level three-dimensional structural features. This framework can be consistently applied to multiple lysine PTM types using a shared modeling strategy. As an application, we used the model to predict potential PTM site on human C-type lectin domain family 12 member A (hCLEC12A) and evaluated their functional relevance through all-atom molecular dynamics simulations. The simulations indicate that the predicted lysine residues influence the stability and binding behavior of the hCLEC12A-antibody 50C1 complex. Overall, this work presents an integrative computational framework for lysine PTM site mining and functional analysis.

Keywords:  deep learning; lysine PTM site mining; molecular dynamics (MD) simulations; protein language model; structural information

DOI:  https://doi.org/10.1073/pnas.2529141123
Metabolism. 2026 Feb 06. pii: S0026-0495(26)00061-2. [Epub ahead of print] 156552

A biological-systems-based analysis using proteomic and metabolic network inference reveals mechanistic insights into hepatic steatosis.

Natalie N Atabaki, Daniel E Coral, Hugo Pomares-Millan, Kieran Smith, Harry H Behjat, Robert W Koivula, Andrea Tura, Hamish Miller, Katherine Pinnick, Leandro Agudelo, Kristine H Allin, Andrew A Brown, Elizaveta Chabanova, Piotr J Chmura, Ulrik P Jacobsen, Adem Y Dawed, Petra J M Elders, Juan J Fernandez-Tajes, Ian M Forgie, Mark Haid, Tue H Hansen, Elizaveta L Hansen, Angus G Jones, Tarja Kokkola, Sebastian Kalamajski, Anubha Mahajan, Timothy J McDonald, Donna McEvoy, Mirthe Muilwijk, Konstantinos D Tsirigos, Jagadish Vangipurapu, Sabine van Oort, Henrik Vestergaard, Jerzy Adamski, Joline W Beulens, Søren Brunak, Emmanouil T Dermitzakis, Giuseppe N Giordano, Ramneek Gupta, Torben Hansen, Leen T Hart, Andrew T Hattersley, Leanne Hodson, Markku Laakso, Ruth J F Loos, Jordi Merino, Mattias Ohlsson, Oluf Pedersen, Martin Ridderstråle, Hartmut Ruetten, Femke Rutters, Jochen M Schwenk, Jeremy Tomlinson, Mark Walker, Hanieh Yaghootkar, Fredrik Karpe, Mark I McCarthy, Elizabeth Louise Thomas, Jimmy D Bell, Andrea Mari, Imre Pavo, Ewan R Pearson, Ana Viñuela, Paul W Franks.

   OBJECTIVE: To delineate organ-specific and systemic drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), we applied integrative causal inference across clinical, imaging, and proteomic domains in individuals with and without type 2 diabetes (T2D).
METHODS: Bayesian network analyses and complementary two-sample Mendelian randomization were used to quantify causal pathways linking adipose distribution, glycemia, and insulin dynamics with liver fat in the IMI-DIRECT prospective cohort study. Data included frequently sampled metabolic challenge tests, MRI-derived abdominal and hepatic fat content, serological biomarkers, and Olink plasma proteomics from 331 adults with new-onset T2D and 964 adults without diabetes, with harmonized protocols enabling replication.
RESULTS: High basal insulin secretion rate (BasalISR), estimated via C-peptide deconvolution, emerged as the primary potential causal driver of liver fat accumulation in both cohorts. BasalISR, a clearance-independent measure of β-cell insulin output distinct from peripheral insulin levels, was independently linked to hepatic steatosis. Visceral adipose tissue exhibited bidirectional associations with liver fat, suggesting a self-reinforcing metabolic loop. Of 446 analyzed proteins, 34 mapped to these metabolic networks (27 in the non-diabetes network, 18 in the T2D network, and 11 shared). Key proteins directly associated with liver fat included GUSB, ALDH1A1, LPL, IGFBP1/2, CTSD, HMOX1, FGF21, AGRP, and ACE2. Sex-stratified analyses identified GUSB in females and LEP in males as the strongest protein predictors of liver fat.
CONCLUSIONS: BasalISR may better capture early β-cell-driven disturbances contributing to MASLD. These findings outline a multifactorial, sex- and disease stage-specific proteo-metabolic architecture of hepatic steatosis and identify potential biomarkers or therapeutic targets.

Keywords:  Basal insulin secretion; Bayesian networks; Hepatic steatosis; MASLD; Mendelian randomization; Proteomics; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.metabol.2026.156552
IEEE Trans Comput Biol Bioinform. 2026 Feb 09. PP

PEGN-PSP:Prediction of General Protein Phosphorylation Sites Using Protein Embeddings and Graph Neural Network.

Shuangshuang Wang, Meiling Liu, Jiyun Zhou.

Phosphorylation ranks among the most crucial post-translational modifications (PTMs), significantly influencing the conformation, activity, and functionality of proteins, and is intricately associated with numerous pathophysiological processes. Therefore, proposing a scientifically valid computational method for precise prediction of phosphorylation sites carries substantial importance. In this study, we propose and evaluate a novel method, PEGN-PSP, based on graph techniques and language models for the prediction of general phosphorylation sites. This method employs an adaptive feature fusion strategy, combining sequence embeddings and pretrained model embeddings to enhance the model's capability in representing features. The use of graph neural network attention mechanisms not only captures local patterns of protein sequences, but also effectively captures long-range dependency information between residues in protein sequences. Independent test results indicate that, in comparison to the current state-of-the-art methods for general phosphorylation site prediction, PEGN-PSP improves the Matthews correlation coefficient for S/T sites by 4.6% and for Y sites by 6.5%. Additionally, PEGN-PSP has good robustness in predicting lysine crotonylation sites, indicating that our method PEGN-PSP has strong potential in predicting other protein posttranslational modification sites. PEGN-PSP is available at https://phos.nebstudio.cn/.

DOI: https://doi.org/10.1109/TCBBIO.2026.3659936
bioRxiv. 2026 Feb 04. pii: 2026.02.02.703178. [Epub ahead of print]

The aging mouse lipidome.

Edgar Esparza, Steven E Pilley, Xuanyi Shi, Preeti Iyengar, Shruti Sivaraman, George Wang, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Aeowynn J Coakley, Ryo Higuchi-Sanabria, Whitaker Cohn, Peter J Mullen.

Aging is associated with widespread metabolic changes that contribute to functional decline and disease. While prior studies have characterized age-associated changes in lipids, it still remains incompletely understood how the lipidome changes across tissues and between sexes during aging. Here, we performed targeted lipidomics across 10 organs collected from male and female mice at five ages spanning adolescence to old age. We analyzed 775 lipids across multiple lipid classes and found that aging affects the lipidome in an organ-specific manner. The thymus and quadriceps muscle had the most age-associated lipid changes, whereas lipid levels in organs such as the kidney and lung remained more stable. In quadriceps muscle, aging was associated with a decrease in specific phosphatidylcholine and phosphatidylethanolamine lipids, particularly those containing adrenic acid. We also identified sex-dependent differences in lipid composition, with the spleen showing differences throughout life. Spleens from female mice had lower levels of lysophosphatidylcholine and lysophosphatidylethanolamine compared to males. Together, these data provide a comprehensive atlas of age- and sex-associated lipid changes across mouse organs and complement existing metabolic and transcriptomic resources to support studies of mouse aging.

DOI: https://doi.org/10.64898/2026.02.02.703178
bioRxiv. 2026 Feb 02. pii: 2026.01.30.702627. [Epub ahead of print]

IDH-mutant inhibitors enhance the sensitivity of IDH1-mutant gliomas to cysteine-methionine deprivation and ferroptosis.

Angeliki Mela, Abby Brand, Aayushi Mahajan, Athanassios Dovas, Nelson Humala, Smriti Kanangat, Allison C Kleinstein, Sandra Leskinen, Trang Tt Nguyen, Qiuqiang Gao, Pavan S Upadhyayula, Jia Guo, Brian Gill, Markus D Siegelin, Peter A Sims, Brent R Stockwell, Jeffrey N Bruce, Peter Canoll.

Cysteine is essential for synthesizing glutathione, the brain's main antioxidant, and cysteine deprivation can trigger ferroptosis. Here, using a new mouse model of IDH1-mutant glioma that recapitulates the characteristics of human IDH1-mutant low-grade gliomas, we demonstrate that IDH1-mutant glioma cells are significantly more vulnerable to cysteine deprivation alone or in combination with the ferroptosis inducer RSL3, compared to IDH1-wildtype glioma cells. In addition, treatments with the IDH-mutant inhibitors vorasidenib and ivosidenib further sensitize the cells to ferroptosis. Metabolomics analysis reveals that IDH1-mutant cells have altered cysteine and methionine metabolism with deficiency in transsulfuration, which is further exacerbated by cysteine-methionine deprivation and IDH-mutant inhibitors. Furthermore, dietary cysteine-methionine deprivation alone or in combination with convection-enhanced delivery of RSL3 or ivosidenib in vivo significantly prolongs survival of IDH1-mutant tumor-bearing mice. Our findings suggest that targeting cysteine and methionine metabolism in combination with IDH-mutant inhibition provides promising therapeutic strategies for IDH1-mutant gliomas.

DOI: https://doi.org/10.64898/2026.01.30.702627
Asian Pac J Cancer Prev. 2026 Feb 01. pii: 92066. [Epub ahead of print]27(2): 613-627

Tumor-Intrinsic PD-1 Regulatory Network Drives Lapatinib Resistance in HER2⁺ Breast Cancer: An Integrative Bioinformatics Analysis.

Ahmed S Alhallaq, Nadeen S Sultan.

   BACKGROUND: Lapatinib resistance evolution in HER2+ breast cancer is still a crucial therapeutic hurdle, with immune microenvironmental reprogramming playing a minimally explored role. Beyond its canonical expression on T cells, programmed cell death protein 1 (PD-1/PDCD1) is intrinsically induced in resistant breast tumors. Through the binding of tumor-intrinsic PD-1 to PD-L1 on adjacent tumor or stromal cells, inhibitory signals are generated, establishing an immunosuppressive microenvironment.
METHODS: This exploratory study investigated the tumor-intrinsic (PD-1)-lapatinib resistance (PLR) regulatory network driving lapatinib resistance in HER2⁺/ER-/PR- breast cancer using an integrative bioinformatics analysis. The GSE38376 dataset and PDCD1 co-expressed genes were utilized to construct the protein-protein interaction (PPI) of the PLR regulatory network. Gene expression patters were visualized using a complex heatmap. Gene ontology, KEGG functional enrichment, gene-metabolite interaction network, immune cell infiltration, comparative gene expression profiling, correlation analysis of PDCD1-hub genes, survival analysis, and genetic alterations analysis were performed on the PLR regulatory network to elucidate the mechanisms of lapatinib resistance.
RESULTS: Pathways and gene-metabolite analyses showed that the PLR regulatory network genes were enriched in immune regulation pathways and lipid metabolic reprogramming. The top 10 PLR-hub genes were identified. Expression profiling in lapatinib-resistant cells revealed the upregulation of PDCD1, B2M, and ITGB2, while other genes, particularly those involved in interferon response and antigen presentation, were downregulated. Immune infiltration analysis indicated exhausted T cells and an immunosuppressive microenvironment. Comparative gene expression and survival analyses of PLR-hub genes implicated the PLR regulatory network in lapatinib resistance. Genetic alterations were infrequent, suggesting that regulation may occur epigenetically or transcriptionally.
CONCLUSION: The findings revealed that the PLR regulatory network is associated with HER2⁺/ER-/PR- lapatinib resistance through multiple mechanisms, including interferon signaling silencing, T cell exhaustion, and the fostering of an immunosuppressive niche. These insights pave the way for interventions aimed at overcoming lapatinib resistance in HER2⁺ breast cancer.

Keywords:  HER2+ breast cancer; Tumor Microenvironment; Tumor-intrinsic PD-1, cancer cell-intrinsic PD-1; lapatinib resistance

DOI:  https://doi.org/10.31557/APJCP.2026.27.2.613
Metab Eng. 2026 Feb 10. pii: S1096-7176(26)00023-6. [Epub ahead of print]95 63-76

Reconstruction of arginine deiminase pathway sustains a higher-energy state in mammalian cells.

Mauro Torres, Matthew Reaney, Kate Meeson, Devika Kalsi, Leon P Pybus, Alan J Dickson.

  ATP is the universal "energy currency" of the cell, and its supply may represent one of several limiting factors influencing the productivity of mammalian cell factories. Here, we present a novel, mitochondria-independent approach to enhance cellular energy metabolism. We engineered Chinese hamster ovary (CHO) cells to express the bacterial arginine deiminase (ADI) pathway along with two arginine transporters. This system enables the direct, cytosolic conversion of arginine to ATP, effectively generating energy without relying solely on the cell's native metabolic machinery. ADI pathway expression was associated with intracellular ATP and concurrent improvements in culture performance across different CHO cell backgrounds. In contrast, cell lines engineered only for enhanced arginine uptake showed no performance gain, consistent with the hypothesis that de-novo ATP generation may contribute to improve productivity. Metabolic profiling revealed that the ADI pathway affects cellular metabolism. We observed a downshift in glycolysis, characterized by decreased glucose consumption and reduced lactate and alanine production, while amino acid and TCA cycle intermediaries remained broadly unchanged. Adenylate measurements and AMPK signalling analysis confirmed a higher energy state (ATP↑, ADP/ATP↓, p-AMPK/AMPK↓) in engineered cells. Supplementing the cell culture medium with arginine or citrulline was associated with further increases in growth and mAb titres in ADI-expressing cells. These results establish the ADI pathway as a powerful and distinct method for enhancing cellular energy. This mitochondria-independent approach highlights a new paradigm for improving the efficiency of industrial bioprocesses.

Keywords:  Arginine deiminase pathway; Biopharmaceuticals; Energy metabolism; Mammalian cells; Metabolic engineering

DOI:  https://doi.org/10.1016/j.ymben.2026.02.004
Cells. 2026 Feb 02. pii: 284. [Epub ahead of print]15(3):

Stress-Inducible Transcription Factor NUPR1 Is Involved in the Inhibitory Effects Exerted by Statins on Insulin Action in ER-Positive Breast Cancer Cells.

Domenica Scordamaglia, Azzurra Zicarelli, Francesca Cirillo, Marianna Talia, Ernestina Marianna De Francesco, Roberta Malaguarnera, Marcello Maggiolini, Rosamaria Lappano.

  Obesity is frequently associated with metabolic alterations like hypercholesterolemia and hyperinsulinemia and represents a major risk factor for several diseases, including breast cancer (BC). Insulin signaling, as well as the frequent overexpression of the insulin receptor (IR), play a key role in BC progression. Emerging evidence suggests that the widely prescribed lipid-lowering drugs, named statins, may reduce the risk of recurrence and blunt BC cell proliferation, mainly inhibiting the HMGCR-dependent activation of the mevalonate pathway. In this study, we investigated the effects of simvastatin, atorvastatin and rosuvastatin in BC cells stimulated by insulin. To this end, we used as a BC model system MCF7 cells and naturally immortalized BCAHC-1 cells, which are characterized by high IR-expression levels. Our investigation demonstrates that statins reduce the proliferation and clonogenic capacity of BC cells prompted by insulin treatment. Mechanistically, statins impair the IR-mediated signaling and downregulate the stress-inducible transcription factor NUPR1, a known regulator of cancer progression. Importantly, NUPR1 inhibition blunted the stimulatory action of insulin on BC cells. Consistent with these findings, survival analyses of large cohorts of patients revealed that high levels of NUPR1 are associated with poor BC prognosis. Overall, our results provide novel mechanistic evidence supporting the repositioning of statins in BC, particularly in tumors characterized by elevated IR expression and activity.

Keywords:  BCAHC-1 cells; breast cancer; insulin; insulin receptor; statins

DOI:  https://doi.org/10.3390/cells15030284
Nat Cell Biol. 2026 Feb 11.

Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis.

Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Marton Horvath, Hugo Talbot, Emma Gustafsson, Stevanus Jonathan, Chaitali Chakraborty, Itzel Nissen, Kelin Gonçalves de Oliveira, Axel Boukredine, Sarah Beyer, Julio Enriquez Perez, Maria C Johansson, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin H van Kuppevelt, Karin Forsberg-Nilsson, Jeffrey D Esko, Silvia Remeseiro, Johan Bengzon, Valeria Governa, Mattias Belting.

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

DOI: https://doi.org/10.1038/s41556-026-01879-y
J Proteome Res. 2026 Feb 12.

An Investigation into the Differentiation of Lactyllysine and Carboxyethyllysine Peptide Modifications by Liquid Chromatography/Mass Spectrometry.

Leigh Donnellan, Clifford Young, Janik D Seidel, Brock Peake, Darren Lau, Permal Deo, Peter Hoffmann.

  Post-translational modifications (PTMs) are key drivers in the regulation of protein activity. Therefore, the ability to measure and identify them accurately is critical to understanding the function and regulation of these modifications. Nε-carboxyethyllysine (CEL) and lactyllysine (LactylLys) are two modifications that share the same chemical composition and thus mass shift, making traditional LC-MS/MS approaches unsuitable for distinguishing them. Standard LC-MS/MS approaches utilizing HCD show that both modifications display extremely similar fragmentation, with no distinguishing features observed for either modification. Furthermore, cyclic and linear immonium ions, which have recently been reported as unique to LactylLys, were also observed in MS/MS from carboxyethylated peptides. We show that carboxyethylated and lactylated peptides can be chromatographically resolved on in-house packed and commercial C18 columns, and retention time alignment with isotopically labeled peptides can be used for discrimination. Furthermore, we observed differences in the MS/MS spectra obtained from EAD fragmentation of the two PTM-containing peptides. Our results highlight the analytical challenges associated with distinguishing CEL- and LactylLys-modified peptides and provide a proof of concept in which retention time alignment of endogenous peptides with isotopically labeled standards and electron activated dissociation (EAD) fragmentation is applied to accurately assign lactylation at K147 of aldolase A across various cell lines/tissues.

Keywords:  LC-MS/MS; Lactyllysine; carboxyethyllysine; electron activated dissociation; post-translational modifications

DOI:  https://doi.org/10.1021/acs.jproteome.5c00969
Cells. 2026 Jan 28. pii: 254. [Epub ahead of print]15(3):

Peroxisomes in Aging: Guardians of Cellular Resilience and Function.

Artuur Vercaemst, Mingming Zhao, Ruizhi Chai, Celien Lismont, Marc Fransen.

  Peroxisomes are multifunctional organelles that play essential roles in lipid metabolism, redox regulation, and cellular signaling. An expanding body of evidence implicates peroxisomal dysfunction as a key contributor to aging and age-related diseases. Aging is accompanied by progressive declines in key peroxisomal functions, including catalase activity, fatty acid β-oxidation, plasmalogen biosynthesis, and the metabolism of bile acids and docosahexaenoic acid, resulting in increased oxidative stress, lipid dysregulation, and alterations in membrane composition. Impaired pexophagy further exacerbates these defects by allowing the accumulation of damaged peroxisomes and compromising cellular homeostasis. Through extensive metabolic and signaling crosstalk with mitochondria, the endoplasmic reticulum, and lysosomes, peroxisomal dysfunction can propagate oxidative and metabolic disturbances throughout the cell. In addition, peroxisome-derived signaling molecules, such as hydrogen peroxide and bioactive lipids, link peroxisomal activity to cellular stress responses and organismal metabolic homeostasis. We propose that aging-associated impairments in peroxisomal protein import, redox regulation, and selective turnover progressively shift peroxisomes from adaptive metabolic signaling hubs toward sources of chronic oxidative and lipid stress. In this context, current studies highlight peroxisomal homeostasis as a potential determinant of healthy aging and point to peroxisomal pathways as emerging targets for intervention in age-related disease.

Keywords:  aging; catalase; interorganelle crosstalk; lipid metabolism; metabolic disorders; neurodegeneration; peroxisomes; pexophagy; reactive oxygen species; therapeutic interventions

DOI:  https://doi.org/10.3390/cells15030254
Cancer Res. 2026 Feb 09.

FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response.

Moumita Banerjee, Yekaterina Y Zaytseva, Ellen M Reusch, Dana L Napier, Sumati Hasani, Piotr Rychahou, Tadahide Izumi, Dennis A Cheek, Jing Li, Robert M Flight, Hunter N B Moseley, Heidi L Weiss, William McCulloch, B Mark Evers, Tianyan Gao.

Altered lipid metabolism is a potential targetable metabolic vulnerability in colorectal cancer (CRC). Fatty acid synthase (FASN), the rate limiting enzyme of de novo lipogenesis, is an important regulator of CRC progression, but the FASN inhibitor TVB-2640 showed only modest efficacy in reducing tumor burden in pre-clinical studies, suggesting combination strategies might be required to prolong patient survival. Here, by using samples from a window trial of TVB-2640 treatment in CRC patients, we found that FASN inhibition induced DNA damage but impaired the DNA damage response (DDR). In colon cancer cell lines and patient-derived organoids, FASN inhibition potentiated chemotherapy-induced double-strand DNA breaks (DSBs) and apoptotic cell death by altering histone acetylation levels. In addition, FASN inhibitor treatment blocked DDR by decreasing ATM expression and CHK2 phosphorylation. Mechanistically, FASN inhibition attenuated activation of the DDR pathway by attenuating BRCA1 and ATM recruitment to -H2AX foci in an acetylation-dependent manner. Moreover, FASN inhibition mediated DNA repair deficiency induced synthetic lethality with PARP inhibition in CRC cells. Importantly, combining FASN inhibition with the chemotherapeutic drug irinotecan synergistically decreased xenograft tumor growth and delayed tumor relapse, which was potentiated by the PARP inhibitor olaparib as maintenance treatment. Taken together, this study describes a therapeutic strategy in which FASN inhibitors can be utilized to delay tumor recurrence after chemotherapy, which is a major challenge in patients with CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1917