bims-mascan Biomed News
on Mass spectrometry in cancer research
Issue of 2025–04–27
35 papers selected by
Giovanny Rodríguez Blanco, Uniklinikum Graz



  1. Angew Chem Int Ed Engl. 2025 Apr 24. e202501884
      Tracing lipid metabolism in mammalian cells presents a significant technological challenge due to the vast structural diversity of lipids involved in multiple metabolic routes. Biorthogonal approaches based on click chemistry have revolutionized analytical performance in lipid tracing. When adapted for mass spectrometry (MS), it enables highly specific and sensitive analyses of lipid transformations at the lipidome scale. Here, we advance this approach by integrating liquid chromatography (LC) prior to MS detection and developing a software-assisted workflow for high-throughput data processing. LC separation resolved labelled and unmodified lipids, enabling qualitative and quantitative analysis of both lipidome fractions, as well as isomeric lipid species. Using synthetic standards and endogenously produced alkyne lipids, we characterized LC-MS behaviour, including preferential adduct formation and extent of in-source fragmentation. Specific fragmentation rules derived from tandem MS experiments for 23 lipid subclasses, were implemented in Lipostar2 software for high-throughput annotation and quantification of labelled lipids. Applying this platform, we traced metabolic pathways of palmitic and oleic acid alkynes, revealing distinct lipid incorporation patterns and metabolic bottlenecks. Altogether, here we provide integrated analytical and bioinformatics platform for high-throughput tracing of lipid metabolism using LC-MS workflow.
    Keywords:  click chemistry * LC-MS * Lipostar2 * sphingolipids * tracing lipid metabolism
    DOI:  https://doi.org/10.1002/anie.202501884
  2. Metabolomics. 2025 Apr 21. 21(3): 54
       INTRODUCTION: The use of large, non-sample specific metabolite reference libraries often results in high proportions of false positive annotations in untargeted metabolomics.
    OBJECTIVE: This study aimed to measure and curate a library of polar metabolites and lipids present in cardiac microtissues.
    RESULTS: Untargeted ultra-high performance liquid chromatography-coupled mass spectrometry measurements of cardiac microtissue intracellular extracts were annotated by comparison against four spectral databases and a retention time library. The annotations were combined to create a library of 313 polar metabolites and 1004 lipids.
    CONCLUSIONS: The curated library will facilitate higher confidence metabolite annotation in mass spectrometry-based untargeted metabolomics of cardiac microtissues.
    Keywords:  Cardiac microtissues; Metabolome annotation; Metabolomics; UHPLC-MS
    DOI:  https://doi.org/10.1007/s11306-025-02252-0
  3. J Proteome Res. 2025 Apr 22.
      Mass spectrometry is essential for analyzing and quantifying biological samples. The timsTOF platform is a prominent commercial tool for this purpose, particularly in bottom-up acquisition scenarios. The additional ion mobility dimension requires more complex data processing, yet most current software solutions for timsTOF raw data are proprietary or closed-source, limiting integration into custom workflows. We introduce rustims, a framework implementing a flexible toolbox designed for processing timsTOF raw data, currently focusing on data-dependent acquisition (DDA-PASEF). The framework employs a dual-language approach, combining efficient, multithreaded Rust code with an easy-to-use Python interface. This allows for implementations that are fast, intuitive, and easy to integrate. With imspy as its main Python scripting interface and sagepy for Sage search engine bindings, rustims enables fast, integrable, and intuitive processing. We demonstrate its capabilities with a pipeline for DDA-PASEF data including rescoring and integration of third-party tools like the Prosit intensity predictor and an extended ion mobility model. This pipeline supports tryptic proteomics and nontryptic immunopeptidomics data, with benchmark comparisons to FragPipe and PEAKS. Rustims is available on GitHub under the MIT license, with installation packages for multiple platforms on PyPi and all analysis scripts accessible via Zenodo.
    Keywords:  DDA-PASEF; Python; framework; ion mobility; mass spectrometry; open-source; proteomics; rust-lang; timsTOF
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00966
  4. STAR Protoc. 2025 Apr 22. pii: S2666-1667(25)00192-3. [Epub ahead of print]6(2): 103786
      Crabtree-positive yeasts rapidly consume glucose via glycolysis, making it difficult to experimentally estimate their actual glycolytic rate or flux. We present a stable isotope labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based protocol to quantitatively estimate glycolytic and related carbon metabolic fluxes using Saccharomyces cerevisiae. This approach defines time windows to capture glucose metabolic intermediate production before label saturation, enabling a comparison of glycolytic flux changes across different cells. This protocol provides a reliable, quantitative approach to study dynamic metabolic fluxes in these cells. For complete details on the use and execution of this protocol, please refer to Vengayil et al., 2024.1.
    Keywords:  metabolism; metabolomics; model organisms; systems biology
    DOI:  https://doi.org/10.1016/j.xpro.2025.103786
  5. J Am Chem Soc. 2025 Apr 23.
      Activity-based protein profiling (ABPP) of stereoisomerically defined sets of electrophilic compounds ('stereoprobes') offers a versatile way to discover covalent ligands for proteins in native biological systems. Here we report the synthesis and chemical proteomic characterization of stereoprobes bearing a P(V)-oxathiaphospholane (OTP) reactive group. ABPP experiments identified numerous proteins in human cancer cells that showed stereoselective reactivity with OTP stereoprobes, and we confirmed several of these liganding events with recombinant proteins. OTP stereoprobes engaging the poorly characterized transmembrane protein TLCD1 impaired the incorporation of monounsaturated fatty acids into phosphatidylethanolamine lipids in cells, a lipidomic phenotype that mirrored genetic disruption of this protein. Using AlphaFold2, we found that TLCD1 structurally resembles the ceramide synthase and fatty acid elongase families of coenzyme A-dependent lipid processing enzymes. This structural similarity included conservation of catalytic histidine residues, the mutation of which blocked the OTP stereoprobe reactivity and lipid remodeling activity of recombinant TLCD1. Taken together, these data indicate that TLCD1 acts as a lipid acyltransferase in cells, and that OTP stereoprobes function as inhibitors of this enzymatic activity. Our findings thus illuminate how the chemical proteomic analysis of electrophilic compounds can facilitate the functional annotation and chemical inhibition of a key lipid metabolic enzyme in human cells.
    DOI:  https://doi.org/10.1021/jacs.5c01944
  6. Nat Commun. 2025 Apr 23. 16(1): 3794
      Advances in proteomics and mass spectrometry enable the study of limited cell populations, where high-mass accuracy instruments are typically required. While triple quadrupoles offer fast and sensitive low-mass specificity measurements, these instruments are effectively restricted to targeted proteomics. Linear ion traps (LITs) offer a versatile, cost-effective alternative capable of both targeted and global proteomics. Here, we describe a workflow using a hybrid quadrupole-LIT instrument that rapidly develops targeted proteomics assays from global data-independent acquisition (DIA) measurements without high-mass accuracy. Using an automated software approach for scheduling parallel reaction monitoring assays (PRM), we show consistent quantification across three orders of magnitude in a matched-matrix background. We demonstrate measuring low-level proteins such as transcription factors and cytokines with quantitative linearity below two orders of magnitude in a 1 ng background proteome without requiring stable isotope-labeled standards. From a 1 ng sample, we found clear consistency between proteins in subsets of CD4+ and CD8+ T cells measured using high dimensional flow cytometry and LIT-based proteomics. Based on these results, we believe hybrid quadrupole-LIT instruments represent a valuable solution to expanding mass spectrometry in a wide variety of laboratory settings.
    DOI:  https://doi.org/10.1038/s41467-025-58757-8
  7. J Proteomics. 2025 Apr 21. pii: S1874-3919(25)00067-3. [Epub ahead of print] 105440
      Intensity-based absolute quantification (iBAQ) is essential in proteomics as it allows for the assessment of a protein's absolute abundance in various samples or conditions. However, the computation of these values for increasingly large-scale and high-throughput experiments, such as those using DIA, TMT, or LFQ workflows, poses significant challenges in scalability and reproducibility. Here, we present ibaqpy (https://github.com/bigbio/ibaqpy), a Python package designed to compute iBAQ values efficiently for experiments of any scale. Ibaqpy leverages the Sample and Data Relationship Format (SDRF) metadata standard to incorporate experimental metadata into the quantification workflow. This allows for automatic normalization and batch correction while accounting for key aspects of the experimental design, such as technical and biological replicates, fractionation strategies, and sample conditions. Designed for large-scale proteomics datasets, ibaqpy can also recompute iBAQ values for existing experiments when an SDRF is available. We showcased ibaqpy's capabilities by reanalyzing 17 public proteomics datasets from ProteomeXchange, covering HeLa cell lines with 4921 samples and 5766 MS runs, quantifying a total of 11,014 proteins. In our reanalysis, ibaqpy is a key component in automating reproducible quantification, reducing manual effort and making quantitative proteomics more accessible while supporting FAIR principles for data reuse. SIGNIFICANCE: Proteomics studies often rely on intensity-based absolute quantification (iBAQ) to assess protein abundance across various biological conditions. Despite its widespread use, computing iBAQ values at scale remains challenging due to the increasing complexity and volume of proteomics experiments. Existing tools frequently lack metadata integration, limiting their ability to handle experimental design intricacies such as replicates, fractions, and batch effects. Our work introduces ibaqpy, a scalable Python package that leverages the Sample and Data Relationship Format (SDRF) to compute iBAQ values efficiently while incorporating critical experimental metadata. By enabling automated normalization and batch correction, ibaqpy ensures reproducible and comparable quantification across large-scale datasets. We validated the utility of ibaqpy through the reanalysis of 17 public HeLa datasets, comprising over 200 million peptide features and quantifying 11,000 proteins across thousands of samples. This comprehensive reanalysis highlights the robustness and scalability of ibaqpy, making it an essential tool for researchers conducting large-scale proteomics experiments. Moreover, by promoting FAIR principles for data reuse and interoperability, ibaqpy offers a transformative approach to baseline protein quantification, supporting reproducible research and data integration within the proteomics community.
    Keywords:  Big data; Bioinformatics; Data integration; Proteomics; Quantification
    DOI:  https://doi.org/10.1016/j.jprot.2025.105440
  8. Mol Cell Proteomics. 2025 Apr 18. pii: S1535-9476(25)00072-6. [Epub ahead of print] 100974
      Relative quantitation, used by most MS-based proteomics laboratories to determine protein fold-changes, requires samples being processed and analyzed together for best comparability through minimizing batch differences. This limits the adoption of MS-based proteomics in population-wide studies, and the detection of subtle but relevant changes in heterogeneous samples. Absolute quantitation circumvents these limitations and enables comparison of results across laboratories, studies, and longitudinally. However, high costs of the essential stable isotope labeled (SIL) standards prevents widespread access and limits the number of quantifiable proteins. Our new approach, called "SysQuan", repurposes SILAC mouse tissues/biofluids as system-wide internal standards for matched human samples to enable absolute quantitation of, theoretically, two-thirds of the human proteome using 157,086 shared tryptic peptides, of which 73,901 with lysine on the c-terminus. We demonstrate that SysQuan enables quantification of 70% and 31% of the liver and plasma proteomes, respectively. We demonstrate for 14 metabolic proteins that abundant SIL mouse tissues enable cost-effective reverse absolute quantitation in, theoretically, 1000s of human samples. Moreover, 10,000s of light/heavy doublets in untargeted SysQuan datasets enable unique post-acquisition absolute quantitation. SysQuan empowers researchers to replace relative quantitation with affordable absolute quantitation at scale, making data comparable across laboratories, diseases and tissues, enabling completely novel study designs and increasing reusability of data in repositories.
    Keywords:  SILAC mice; absolute quantitation; multiplexing; stable isotope labeling; targeted and untargeted quantitation
    DOI:  https://doi.org/10.1016/j.mcpro.2025.100974
  9. Methods Mol Biol. 2025 ;2919 67-82
      Histone proteins are the structural components of nucleosomes, which form chromatin. Histone proteins are typically modified with many posttranslational modifications (PTMs), which affect chromatin accessibility, and by extension, modulate gene transcription, and other DNA-related processes. Mass spectrometry has become the reference technology to quantify global levels of hundreds of histone PTMs in single experiments. The advancement of high throughput has paved the way to new possibilities, including experimental design that include large cohort of samples. In this chapter, we describe a protocol for the unbiased analysis of histone PTMs assisted by a robotic liquid handler. The implementation of a simple-to-use script for automated histone derivatization and digestion reduces the number of manual steps needed to prepare histone peptides for mass spectrometry analysis and improves consistency of resulting data.
    Keywords:  Automation; Chromatin; Histones; Mass spectrometry; Posttranslational modifications
    DOI:  https://doi.org/10.1007/978-1-0716-4486-7_4
  10. Anal Chim Acta. 2025 Jun 08. pii: S0003-2670(25)00397-6. [Epub ahead of print]1354 344003
       BACKGROUND: Palmitate, which is the end product of fatty acid synthase, is the key fatty acid for understanding of lipid biosynthetic process in mammalian cells. Mass spectrometry (MS) methodology using 13C-palmitate can trace the lipid biosynthesis such as glycerolipids, glycerophospholipids, and sphingolipids. However, due to the interferences of natural heavy isotopes, accurate measurement of 13C-labeled lipid species has been limited. Here we describe a high-throughput isotope tracing experiment to assess lipid biosynthesis using parallel reaction monitoring-MS (PRM-MS) with 13C16-palmitate as an isotope tracer.
    RESULTS: The developed method can trace 14 13C16-labeled lipid classes without disturbance from the heavy isotope patterns of natural lipids. Lipid class-based separation was achieved through hydrophilic interaction liquid chromatography (HILIC) which allows facile identification of lipid, and PRM-MS was performed for accurate detection of the 13C16-labeled lipids. A fibroblast (NIH/3T3) cell line was used as an in vitro model, and the NIH/3T3 cells were treated with bovine serum albumin (BSA)-bound 13C16-palmitate. The isotopic disturbance from natural lipid was eliminated using 13C16-palmitate, rather than 13C1-palmitate, as an isotope tracer. After 24 h of incubation with 0.1 mmol/L of BSA-bound 13C16-palmitate in the fibroblasts, NIH/3T3 cells synthesized the 127 13C16-labeled lipid species of glycerolipids, glycerophospholipids, and sphingolipids. Finally, in the NIH/3T3 cells incubated for 1, 6, and 24 h after the treatment of the isotope tracer exhibited an increased profile of 13C16-labeled lipidome, depending on duration of incubation.
    SIGNIFICANCE: The HILIC/PRM-MS method using 13C16-palmitate as an isotope tracer enables identification of 13C16-labeled lipid species by annotating 13C16-labeled position, including the 13C16-fatty acyl chain and 13C16-sphingolipid headgroup, without interference of natural heavy isotope patterns. This lipidomic flux analysis using PRM approach is expected to provide insights into assessment of isotope-labeled lipids.
    Keywords:  HILIC-MS/MS; Isotope tracing; Lipid biosynthesis; Lipidomics; Parallel reaction monitoring
    DOI:  https://doi.org/10.1016/j.aca.2025.344003
  11. Trends Analyt Chem. 2023 Dec;pii: 117350. [Epub ahead of print]169
      In the past decade, lipidomics, now recognized as standalone subdiscipline of metabolomics, has gained considerable attention. Due to its sensitivity and unparalleled versatility, mass spectrometry (MS) has emerged as the tool of choice for lipid identification and detection. Traditional MS-based lipidomics are performed on bulk cell samples. While informative, these bulk-scale cellular lipidome measurements mask cellular heterogeneity across seemingly homogeneous populations of cells. Unfortunately, single cell lipidomics methodology and analyses are considerably behind genomics, transcriptomics, and proteomics. Therefore, the cell-to-cell heterogeneity and related function remains largely unexplored for lipidomics. Herein, we review recent advances in MS-based single cell lipidomics. We also explore the root causes for the slow development of single-cell lipidomics techniques. We aim to provide insights on the pivotal knowledge gaps that have been neglected, prohibiting the propulsion of the single-cell lipidomics field forward, while also providing our perspective towards future methodologies that can pave a path forward.
    Keywords:  Matrix-Assisted Laser Desorption/Ionization; ambient ionization; bioanalysis; cellular; cellular heterogeneity; data analysis; electrospray ionization; lipidomics; machine learning; mass spectrometry; mass spectrometry imaging; metabolomics; omics technologies; single-cell analysis; subcellular analysis; tandem mass spectrometry
    DOI:  https://doi.org/10.1016/j.trac.2023.117350
  12. Mass Spectrom Rev. 2025 Apr 23.
      Cancer is the leading cause of death worldwide characterized by patient heterogeneity and complex tumor microenvironment. While the genomics-based testing has transformed modern medicine, the challenge of diverse clinical outcomes highlights unmet needs for precision oncology. As functional molecules regulating cellular processes, proteins hold great promise as biomarkers and drug targets. Mass spectrometry (MS)-based clinical proteomics has illuminated the molecular features of cancers and facilitated discovery of biomarkers or therapeutic targets, paving the way for innovative strategies that enhance the precision of personalized treatment. In this article, we introduced the tools and current achievements of MS-based proteomics, choice of discovery and targeted MS from discovery to validation phases, profiling sensitivity from bulk samples to single-cell level and tissue to liquid biopsy specimens, current regulatory landscape of MS-based protein laboratory-developed tests (LDTs). The challenges, success and future perspectives in translating research MS assay into clinical applications are also discussed. With well-designed validation studies to demonstrate clinical benefits and meet the regulatory requirements for both analytical and clinical performance, the future of MS-based assays is promising with numerous opportunities to improve cancer diagnosis, treatment, and monitoring.
    Keywords:  biomarker; laboratory developed tests (LDTs); mass spectrometry; precision oncology; proteomics; single‐cell proteomics
    DOI:  https://doi.org/10.1002/mas.21932
  13. J Proteome Res. 2025 Apr 23.
      Scientific discovery relies on innovative software as much as experimental methods, especially in proteomics, where computational tools are essential for mass spectrometer setup, data analysis, and interpretation. Since the introduction of SEQUEST, proteomics software has grown into a complex ecosystem of algorithms, predictive models, and workflows, but the field faces challenges, including the increasing complexity of mass spectrometry data, limited reproducibility due to proprietary software, and difficulties integrating with other omics disciplines. Closed-source, platform-specific tools exacerbate these issues by restricting innovation, creating inefficiencies, and imposing hidden costs on the community. Open-source software (OSS), aligned with the FAIR Principles (Findable, Accessible, Interoperable, Reusable), offers a solution by promoting transparency, reproducibility, and community-driven development, which fosters collaboration and continuous improvement. In this manuscript, we explore the role of OSS in computational proteomics, its alignment with FAIR principles, and its potential to address challenges related to licensing, distribution, and standardization. Drawing on lessons from other omics fields, we present a vision for a future where OSS and FAIR principles underpin a transparent, accessible, and innovative proteomics community.
    Keywords:  FAIR principles; best practices; computational proteomics; data reuse; mass spectrometry; open data; open source; proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.4c01079
  14. Cell Rep. 2025 Apr 19. pii: S2211-1247(25)00367-5. [Epub ahead of print]44(5): 115596
      Understanding the mechanisms by which oncogenic events alter metabolism will help identify metabolic weaknesses that can be targeted for therapy. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance in most cancers. Here, we show that TERT acts via the transcription factor forkhead box O1 (FOXO1) to upregulate glutamate-cysteine ligase (GCLC), the rate-limiting enzyme for de novo biosynthesis of glutathione (GSH, reduced) in multiple cancer models, including glioblastoma (GBM). Genetic ablation of GCLC or pharmacological inhibition using buthionine sulfoximine (BSO) reduces GSH synthesis from [U-13C]-glutamine in GBMs. However, GCLC inhibition drives de novo pyrimidine nucleotide biosynthesis by upregulating the glutamine-utilizing enzymes glutaminase (GLS) and carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotatase (CAD) in an MYC-driven manner. Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs.
    Keywords:  CP: Cancer; CP: Metabolism; TERT; brain tumors; cancer; glioblastoma; glutamine metabolism; glutathione; in vivo stable isotope tracing; metabolic synthetic lethality; metabolomics; nucleotide biosynthesis; telomerase reverse transcriptase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115596
  15. Anal Chim Acta. 2025 Jun 15. pii: S0003-2670(25)00399-X. [Epub ahead of print]1355 344005
       BACKGROUND: Isotope tracing experiments in cellular metabolomics are challenged by the multiple isomers and in-source fragments, which need to be considered to obtain unbiased isotopologue ratio measurements. Thus, both, selectivity and sensitivity are key requirements for customized workflows. Trapped ion mobility spectrometry (TIMS) introduces an additional separation dimension to mass spectrometry, separating otherwise co-eluting isomers by measuring the ion mobility of a molecule. This study shows for the first time, the potential of this MS platform for accurate isotopologue assessment as showcased in isotope tracer experiments using mammalian cells.
    RESULTS: The validation exercise focused on spectral accuracy, precision, and metabolite detection capabilities and comprised independent measurements on an orbitrap-based platform. Hydrophilic interaction chromatography, in combination with TIMS-TOF-MS delivered excellent results, with a minimum trueness bias and excellent precision (CV%) between 0.3 % and 6.4 %. The ion mobility separation allowed for differentiation of the otherwise co-eluting isomers fructose-6-phosphate (F6P) and glucose-1-phosphate (G1P). Overall, isotopologue distributions were in good agreement upon crossvalidation with the orbitrap platform. Finally, a proof-of-concept tracer study addressed the activity of the glycolysis and the pentose phosphate pathway (PPP) in resting and endotoxin activated macrophages. We confirmed an activation of glycolysis and PPP in LPS activated macrophages, but found a potentially reduced relative contribution of glucose-6-phosphate (G6P) to increased F6P pools. Our findings imply that TIMS is a powerful technology for the reliable measurements of isotope distribution analysis in metabolic tracing experiments.
    SIGNIFICANCE: By implementation of ion mobility, it is now possible to generate distinct isotopologue patterns for G1P and F6P in isotope tracer experiments. F6P plays a crucial role in glycolysis and PPP, highlighting the importance of precise analytical measurements. This is particularly true for metabolic studies in immunology and cancer research.
    Keywords:  Isotope tracer; Macrophages; TIMS; Trapped ion mobility
    DOI:  https://doi.org/10.1016/j.aca.2025.344005
  16. J Proteome Res. 2025 Apr 21.
      We have developed an automated cell-based workflow for the quantification of proteins by liquid chromatography-mass spectrometry (LC-MS) that facilitates large-scale perturbation studies carried out in a 96-well plate format and enables the preparation of one full plate in approximately 4 h, showcasing a high-throughput (HTP) concept. Cells were grown in a 96-well plate and lysed via ultrasonication. Proteins were subsequently solubilized, extracted, and processed into tryptic peptides for 2 h before being acquired by data-independent acquisition mass spectrometry (DIA-MS). This workflow leverages adaptive focused acoustics (AFA) technology for ultrasonication to aid cell lysis and protein solubilization on an automated liquid handling platform. As proof of principle, AC16 human cardiomyocyte-like cells were cultured in a 96-well plate under optimized conditions that were compatible with the downstream HTP pipeline. Over 30,000 peptides were identified, corresponding to the detection of 5100 unique proteins. 50% of measured proteins had an average coefficient of variation (CV) under 25% from approximately 30,000 cells. Our optimized detergent-free buffer consisting of ammonium bicarbonate yielded comparable findings. For the same number of cells, 5000 proteins were identified from 29,000 peptides, 40% of which demonstrated a CV under 25%.
    Keywords:  cell-based assay; detergent-free; high-throughput; hypoxia and reperfusion; mitochondria; myocardial ischemia; perturbation; protein extraction workflow
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00892
  17. J Sep Sci. 2025 Apr;48(4): e70147
      Steroids are a major set of endogenous bioactive compounds. Although increasingly popular, their analysis in biofluids by LC-MS is associated with enduring challenges, such as their low endogenous concentrations or the coexistence of numerous isobaric compounds. Their natural presence in biological matrices complicates their absolute quantification in blood, as the obtention of a blank matrix to establish an external calibration curve is impossible. This protocol describes a strategy for developing an LC-MS/MS method for the extended profiling of steroids in serum and plasma, including as much as 171 target compounds, with the additional absolute quantification of four main steroids (cortisol, testosterone, progesterone, and androstenedione). The proposed sample preparation involves protein precipitation in organic solvents and subsequent filtration of the sample on HLB cartridge. The LC method is developed to resolve most isobaric species thanks to a biphenyl stationary phase. MS detection is performed in multiple reaction monitoring mode with post-column addition of ammonium fluoride to enhance sensitivity. A one-point internal calibration strategy is presented for the absolute quantification of endogenous steroids. The application of this method to the NIST Plasma Reference Material (SRM 1950) led to the identification of 69 distinct endogenous steroids, making it the most comprehensive profiling of these compounds in this reference matrix to date. The quantitative performance of the method is assessed with two certified materials and shows satisfactory precision and trueness.
    Keywords:  absolute quantification; endogenous compounds; liquid chromatography; mass spectrometry; steroids
    DOI:  https://doi.org/10.1002/jssc.70147
  18. Metabolites. 2025 Apr 05. pii: 250. [Epub ahead of print]15(4):
      Background/Objectives: Millions of new diagnoses of breast cancer are made each year, with many cases having poor prognoses and limited treatment options, particularly for some subtypes such as triple-negative breast cancer. Resveratrol, a naturally occurring polyphenol, has demonstrated many anticancer properties in breast cancer studies. However, the mechanism of action of this compound remains elusive, although prior evidence suggests that this compound may work through altering cancer cell metabolism. Our objective for the current study was to perform untargeted metabolomics analysis on resveratrol-treated breast cancer cells to identify key metabolic targets of this compound. Methods: MCF-7 and MDA-MB-231 breast cancer cells were treated with varying doses of resveratrol and extracted for mass spectrometry-based untargeted metabolomics. Data preprocessing and filtering of metabolomics data from MCF-7 samples yielded 4751 peaks, with 312 peaks matched to an in-house standards library and 3459 peaks matched to public databases. Results: Pathway analysis in MetaboAnalyst identified significant (p < 0.05) metabolic pathways affected by resveratrol treatment, particularly those involving steroid, fatty acid, amino acid, and nucleotide metabolism. Evaluation of standard-matched peaks revealed acylcarnitines as a major target of resveratrol treatment, with long-chain acylcarnitines exhibiting a 2-5-fold increase in MCF-7 cells and a 5-13-fold increase in MDA-MB-231 cells when comparing the 100 µM treated cells to vehicle-treated cells (p < 0.05, VIP > 1). Notably, doses below 10 µM showed an opposite effect, possibly indicating a biphasic effect of resveratrol due to a switch from anti-oxidant to pro-oxidant effects as dose levels increase. Conclusions: These findings suggest that resveratrol induces mitochondrial metabolic reprogramming in breast cancer cells in a dose-dependent manner. The biphasic response indicates a potential optimal dosage for therapeutic effectiveness. Further research is warranted to explore the mechanisms underlying these metabolic alterations and their implications for precision nutrition strategies in cancer treatment.
    Keywords:  breast cancer; metabolomics; mitochondria; resveratrol; triple-negative
    DOI:  https://doi.org/10.3390/metabo15040250
  19. Methods Mol Biol. 2025 ;2919 251-266
      Histone proteins regulate essential cellular processes by being decorated with a myriad of posttranslational modifications (PTMs). These processes are mostly led by the ability of these PTMs to recruit protein readers involved in gene transcription, DNA replication, DNA damage, chromatin remodeling, and other functions. Identifying histone readers is critical for the understanding of mechanisms leading to these functions and potentially predict targets for treatment in anomalous phenotypes. For this reason, histone reader identification has been performed for several years using strategies aiming to increase depth, resolution, and accuracy, e.g., ChIP-MS, proximity biotinylation, photo-crosslinking, and array-based technologies. In this chapter, we describe a protocol for identifying histone readers in a straightforward and unbiased manner: peptide pull-down combined with high-resolution mass spectrometry. Synthesized and immobilized modified histone peptides are incubated with nuclear extracts, and the PTMs' interactors are analyzed by mass spectrometry, which allows the identification of thousands of proteins with high confidence. We also describe the steps for a proteomic data analysis and present tools for a comprehensive data integration.
    Keywords:  Chromatin; Mass spectrometry; Peptide pull–down; Protein–protein interactions; Proteomics
    DOI:  https://doi.org/10.1007/978-1-0716-4486-7_14
  20. Nat Methods. 2025 Apr 22.
      Proteomic workflows generate vastly complex peptide mixtures that are analyzed by liquid chromatography-tandem mass spectrometry, creating thousands of spectra, most of which are chimeric and contain fragment ions from more than one peptide. Because of differences in data acquisition strategies such as data-dependent, data-independent or parallel reaction monitoring, separate software packages employing different analysis concepts are used for peptide identification and quantification, even though the underlying information is principally the same. Here, we introduce CHIMERYS, a spectrum-centric search algorithm designed for the deconvolution of chimeric spectra that unifies proteomic data analysis. Using accurate predictions of peptide retention time, fragment ion intensities and applying regularized linear regression, it explains as much fragment ion intensity as possible with as few peptides as possible. Together with rigorous false discovery rate control, CHIMERYS accurately identifies and quantifies multiple peptides per tandem mass spectrum in data-dependent, data-independent or parallel reaction monitoring experiments.
    DOI:  https://doi.org/10.1038/s41592-025-02663-w
  21. Spectrochim Acta A Mol Biomol Spectrosc. 2025 Apr 19. pii: S1386-1425(25)00581-5. [Epub ahead of print]339 126275
      Cellular respiration is the primary metabolic process for producing the energy (ATP) needed for survival. Disruptions in this process can lead to various diseases, including colon cancer. This paper reviews the current understanding of how excess fatty acids (FAs) and glucose (Glc) alter metabolic pathways. We focused on the impact of unsaturated fatty acids (UFAs) (eicosapentaenoic acid (EPA), linoleic acid (LA)), saturated fatty acid (SFA) (palmitic acid (PA)), and glucose on healthy human colon cells (CCD-18 Co) and cancerous colon cells (Caco-2) using Raman microspectroscopy. Our study examined the metabolic abnormalities in mitochondria and lipid droplets caused by the external intake of FAs and glucose. The results indicate that the peaks at 750 cm-1, 1004 cm-1, 1256 cm-1, 1444 cm-1, and 1656 cm-1 can serve as Raman biomarkers for monitoring metabolic pathways in colon cancer. We proved that oxidative metabolism towards glycolysis allows maintaining redox homeostasis and enables the survival and proliferation of cancer cells in hypoxic conditions. Our findings show that comparing control cells with cells supplemented with UFAs, SFA, and glucose can help detect metabolic abnormalities. Specifically, supplementation with UFAs reduces the intensity of the bands at 750 cm-1 and 1004 cm-1, while SFA and glucose increase their intensity. For the bands at 1256 cm-1, 1444 cm-1, and 1656 cm-1, palmitic acid and glucose decrease the intensity, whereas linoleic acid increases it. This paper introduces new experimental techniques, such as Raman microspectroscopy and imaging, to track and understand the metabolic changes in colon cells caused by FAs and glucose under hypoxic conditions.
    Keywords:  Colon cancer biomarkers; Fatty acids; Glucose; Hypoxia; Raman microspectroscopy
    DOI:  https://doi.org/10.1016/j.saa.2025.126275
  22. Semin Nephrol. 2025 Apr 21. pii: S0270-9295(25)00020-8. [Epub ahead of print] 151583
      In the last decade, advanced developments of mass spectrometry-based assays have made spatial measurements of hundreds of metabolites and thousands of proteins not only possible, but routine. The information obtained from such mass spectrometry imaging experiments traces metabolic events and helps decipher feedback loops across anatomical regions, connecting genetic and metabolic networks that define phenotypes. Herein we overview developments in the field over the past decade, highlighting several case studies demonstrating direct measurement of metabolites, proteins, and proteoforms from thinly sliced tissues at the level of functional tissue units, approaching single-cell levels. Much of this work is feasible due to multidisciplinary team science, and we offer brief perspectives on paths forward and the challenges that persist with adoption and application of these spatial omics techniques at the single-cell level on mammalian kidneys. Data analysis and reanalysis still pose issues that plague spatial omics, but many mass spectrometry imaging platforms are commercially available. With greater harmonization across platforms and rigorous quality control, greater adoption of these platforms will undoubtedly provide major insights in complex diseases. Semin Nephrol 36:x-xx © 20xx Elsevier Inc. All rights reserved.
    Keywords:  Mass spectrometry; metabolomics; multimodal analyses; proteomics; spatial omics
    DOI:  https://doi.org/10.1016/j.semnephrol.2025.151583
  23. Metabolites. 2025 Apr 17. pii: 277. [Epub ahead of print]15(4):
      Background/Objectives: Cancer cells often display altered energy metabolism. In particular, expression levels and activity of the tricarboxylic acid cycle (TCA cycle) enzymes may change in cancer, and dysregulation of the TCA cycle is a frequent hallmark of cancer cell metabolism. MEMO1, a modulator of cancer metastasis, has been shown to bind iron and regulate iron homeostasis in the cells. MEMO1 knockout changed mitochondrial morphology and iron content in breast cancer cells. Our previous genome-wide analysis of MEMO1 genetic interactions across multiple cancer cell lines revealed that gene sets involved in mitochondrial respiration and the TCA cycle are enriched among the gain-of-function interaction partners of MEMO1. Based on these findings, we measured the TCA cycle metabolite levels in breast cancer cells with varying levels of MEMO1 expression. Methods: ShRNA knockdown assay was performed to test essentiality of key TCA cycle enzymes. TCA metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in MDA-MB-231 (high MEMO1), M67-2 (MEMO1 knockdown), and M67-9 (MEMO1 knockout) cells under iron-depleted, basal iron, and iron-supplemented conditions. Results:ACO2 and OGDH knockdowns inhibit cell proliferation, indicating an essential role of the TCA cycle in MDA-MB-231 metabolism. α-Ketoglutarate and citrate levels exhibited an inverse relationship with MEMO1 expression, increasing significantly in MEMO1 knockout cells regardless of iron availability. In contrast, fumarate, malate, and glutamate levels were elevated in MEMO1 knockout cells specifically under low iron conditions, suggesting an iron-dependent effect. Conclusions: Overall, our results indicate that MEMO1 plays a role in regulating the TCA in cancer cells in an iron-dependent manner.
    Keywords:  LC-MS/MS; MEMO1; breast cancer; cancer metastasis; energy metabolism; iron regulation; metal binding protein; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3390/metabo15040277
  24. J Lipid Res. 2025 Apr 18. pii: S0022-2275(25)00073-2. [Epub ahead of print] 100813
      Sphingolipids and glycosphingolipids are among the most structurally diverse and complex compounds in the mammalian metabolome. They are well known to play important roles in biological architecture, cell-cell communication and cellular regulation, and for many biological processes, multiple sphingolipids are involved. Thus, it is not surprising that untargeted genetic/transcriptomic/pharmacologic/metabolomic screens have uncovered changes in sphingolipids and sphingolipid genes/proteins while studying physiological and pathological processes. Consequently, with increasing frequency, both targeted and untargeted mass spectrometry methodologies are being used to conduct sphingolipidomic analyses. Interpretation of such large data sets and design of follow-up experiments can be daunting for investigators with limited expertise with sphingolipids (and sometimes even for someone well-versed in sphingolipidology). Therefore, this review gives an overview of essential elements of sphingolipid structure and analysis, metabolism, functions, and roles in disease, and discusses some of the items to consider when interpreting lipidomics data and designing follow-up investigations.
    Keywords:  Pathway analysis; Targeted lipidomics; Untargeted lipidomics
    DOI:  https://doi.org/10.1016/j.jlr.2025.100813
  25. Front Oncol. 2025 ;15 1509662
      Serine is crucial for tumor initiation, progression, and adaptive immunity. Metabolic pathways for serine synthesis, acquisition, and utilization in tumors and tumor-associated cells are influenced by various physiological factors and the tumor microenvironment, leading to metabolic reprogramming and amplification. Excessive serine metabolism promotes abnormal macromolecule biosynthesis, mitochondrial dysfunction, and epigenetic modifications, driving malignant transformation, proliferation, metastasis, immune suppression, and drug resistance in tumor cells. Restricting dietary serine intake or reducing the expression of serine synthetic enzymes can effectively slow tumor growth and extend patient survival. Consequently, targeting serine metabolism has emerged as a novel and promising research focus in cancer research. This paper reviews serine metabolic pathways and their roles in tumor development. It summarizes the influencing factors of serine metabolism. The article explores the significance of serine synthesis and metabolizing enzymes, along with related biomarkers, in tumor diagnosis and treatment, providing new insights for developing targeted therapies that modulate serine metabolism in cancer.
    Keywords:  cancer; one-carbon metabolism; serine catabolism; serine metabolism; the immunosuppressive microenvironment
    DOI:  https://doi.org/10.3389/fonc.2025.1509662
  26. Trends Cancer. 2025 Apr 23. pii: S2405-8033(25)00076-7. [Epub ahead of print]
      Tryptophan (Trp) is an essential amino acid and key intermediate in a range of biological processes. Early studies identified altered Trp utilization in cancer cells favoring cancer survival and growth. Seminal findings linking Trp metabolism and suppression of immunity led to an explosion of interest ultimately culminating in clinical trials targeting these pathways in melanoma. The failure of these trials led to a clinical retreat in this approach; however, recent insights into the complex interplay of the various Trp circuits and between tumor cells, immune cells, and the microbiota have shown that reconsideration of Trp metabolism is needed. Here, we discuss recent developments in our understanding of Trp metabolism and apparent contradictions in the field. We also discuss adaptations that occur when Trp pathways are manipulated, which may impact therapy responses.
    Keywords:  kynurenine; metabolism; microbiome; tryptophan; tumor immunity
    DOI:  https://doi.org/10.1016/j.trecan.2025.03.008
  27. Anal Chem. 2025 Apr 20.
      Here, we introduce Met-ID, a graphical user interface software designed to efficiently identify metabolites from MALDI-MSI data sets. Met-ID enables annotation of m/z features from any type of MALDI-MSI experiment, involving either derivatizing or conventional matrices. It utilizes structural information for derivatizing matrices to generate a subset of targets that contain only functional groups specific to the derivatization agent. The software is able to identify multiple derivatization sites on the same molecule, facilitating identification of the derivatized compound. This ability is exemplified by FMP-10, a reactive matrix that assists the covalent charge-tagging of molecules containing phenolic hydroxyl and/or primary or secondary amine groups. Met-ID also permits users to recalibrate data with known m/z ratios, boosting confidence in mass match results. Furthermore, Met-ID includes a database featuring MS2 spectra of numerous chemical standards, consisting of neurotransmitters and metabolites derivatized with FMP-10, alongside peaks for FMP-10 itself, all accessible directly through the software. The MS2 spectral database supports user-uploaded spectra and enables comparison of these spectra with user-provided tissue MS2 spectra for similarity assessment. Although initially installed with basic data, Met-ID is designed to be customizable, encouraging users to tailor the software to their specific needs. While several MSI-oriented software solutions exist, Met-ID combines both MS1 and MS2 functionalities. Developed in alignment with the FAIR Guiding Principles for scientific software, Met-ID is freely available as an open-source tool on GitHub, ensuring wide accessibility and collaboration.
    DOI:  https://doi.org/10.1021/acs.analchem.5c00633
  28. J Am Soc Mass Spectrom. 2025 Apr 21.
      Derivatization of unsaturated fatty acids with dimethyl disulfide (DMDS) and analysis by electron ionization mass spectrometry (EIMS) represent a convenient offline method for the identification of double bond positions. However, the presence of overlapping mass spectra from multiple compounds poses significant challenges for spectral interpretation and library matching, leading to ambiguous molecular information and low sensitivity. To overcome the issue, we developed a novel chemical ionization (CI) tandem mass spectrometry method involving the pre-derivatization with DMDS and collisional activation of [M+47]+ ions generated in the chemical ion source. The method provides better specificity to the analysis of targeted fatty acids and does not require any customized devices. Further, a multiple reaction monitoring (MRM) version of the method was designed by screening all the diagnostic ions of possible double bond positional isomers, which significantly boosts the sensitivity. Compared to the traditional EIMS method, the new method exhibits a lower limit of detection (LLOD) that is one-tenth or lower. Employing the new method, unusual isomer 18:2(5Z,8Z) was co-analyzed with 18:2(9Z,12Z), and a novel 20:2(7Z,10Z) was characterized in human sebum. Additionally, 16:2(9Z,12Z), an odd-chain omega-3 polyunsaturated fatty acid (21:5n-3) and polymethylene-interrupted isomers, i.e. 22:2(7Z,13Z) and 22:2(7Z,15Z) were identified in seafood and related products. Our method can be readily applied to any GC instrument equipped with tandem MS and is expected to facilitate the discovery and identification of unknown fatty acids from food, clinical, and environmental sources.
    Keywords:  Carbon−carbon double bond; Chemical ionization; Dimethyl disulfide; Mass spectrometry; Unsaturated fatty acid
    DOI:  https://doi.org/10.1021/jasms.5c00033
  29. Metabolites. 2025 Mar 25. pii: 222. [Epub ahead of print]15(4):
       BACKGROUND/OBJECTIVES: Gastric cancer (GC) is a prevalent malignant tumor worldwide, with its pathological mechanisms largely unknown. Understanding the metabolic reprogramming associated with GC is crucial for the prevention and treatment of this disease. This study aims to identify significant alterations in metabolites and pathways related to the development of GC.
    METHODS: A liquid chromatography-mass spectrometry-based non-targeted metabolomics data acquisition was performed on paired tissues from 80 GC patients. Differences in metabolic profiles between tumor and adjacent normal tissues were first investigated through univariate and multivariate statistical analyses. Additionally, differential correlation network analysis and a newly proposed network analysis method (NAM) were employed to explore significant metabolite pathways and subnetworks related to tumorigenesis and various TNM stages of GC.
    RESULTS: Over half of the annotated metabolites exhibited significant alterations. Phosphatidylcholine (PC)_30_0 and fatty acid C20_3 demonstrated strong diagnostic performance for GC, with AUCs of 0.911 and 0.934 in the discovery and validation sets, respectively. Differential correlation network analysis revealed significant fatty acid-related metabolic reprogramming in GC with elevated levels of medium-chain acylcarnitines and increased activity of medium-chain acyl-CoA dehydrogenase, firstly observed in clinical GC tissues. Of note, using NAM, two correlation subnetworks were identified as having significant alterations across different TNM stages, centered with choline and carnitine C4_0-OH, respectively.
    CONCLUSIONS: The identified significant alterations in fatty acid metabolism and TNM-related metabolic subnetworks in GC tissues will facilitate future investigations into the metabolic reprogramming associated with gastric cancer.
    Keywords:  fatty acid β-oxidation; gastric cancer; metabolic reprogramming; metabolomics
    DOI:  https://doi.org/10.3390/metabo15040222
  30. Poult Sci. 2025 Apr 19. pii: S0032-5791(25)00441-9. [Epub ahead of print]104(7): 105199
      This review highlights that utilization of dietary amino acids for energy metabolism in broiler chickens imposes a metabolic cost, as their primary role is to support body protein synthesis. This issue becomes more critical in reduced-crude protein (CP) diets. When amino acids are used as fuel for enterocytes or undergo catabolism in the liver, they are diverted from body protein accretion. Catabolism of amino acids for energy generates α-keto acids and ammonia. α-Keto acids can be fully oxidized to produce ATP or converted into pyruvate, ketone bodies, and intermediates of the tricarboxylic acid cycle. Meanwhile, ammonia must be detoxified through the uric acid cycle, a process that requires energy, glycine, and aspartic acid. Derivatives of α-keto acids can contribute to gluconeogenesis and de novo lipogenesis, leading to glucose and fatty acid synthesis, respectively. The α-keto acid derivatives are more likely to undergo de novo lipogenesis in broilers, as evidenced by consolidated data in this review. However, de novo lipogenesis is also an energy-intensive process. Therefore, enhancing the efficiency of dietary amino acid conversion to body protein requires reducing their utilization for energy metabolism. This may be achieved through dietary manipulations, as previous studies indicate that amino acid catabolism in enterocytes and the liver is influenced by starch and protein digestive dynamics, dietary amino acid compositions, and the primary feed grain used in diets. In reduced-CP broiler diets, supplementation of glutamic acid and potentially glutamine, aspartic acid, and proline could mitigate the catabolism of essential amino acids in enterocytes. Additionally, moderating starch digestion rates may reduce amino acid catabolism in enterocytes. Moreover, optimizing the balance of dietary protein-bound and non-bound amino acids could minimize amino acid catabolism in the liver. In summary, reducing the contribution of amino acids to energy metabolism in broiler chickens is particularly beneficial in reduced-CP diets, ultimately supporting more sustainable chicken meat production.
    Keywords:  Amino acid catabolism; Broiler; Energy; Lipogenesis
    DOI:  https://doi.org/10.1016/j.psj.2025.105199
  31. Metabolites. 2025 Mar 24. pii: 221. [Epub ahead of print]15(4):
      Background/Objectives: Endoplasmic reticulum (ER) stress occurs when ER homeostasis is disrupted, leading to the accumulation of misfolded or unfolded proteins. This condition activates the unfolded protein response (UPR), which aims to restore balance or trigger cell death if homeostasis cannot be achieved. In cancer, ER stress plays a key role due to the heightened metabolic demands of tumor cells. This review explores how metabolomics can provide insights into ER stress-related metabolic alterations and their implications for cancer therapy. Methods: A comprehensive literature review was conducted to analyze recent findings on ER stress, metabolomics, and cancer metabolism. Studies examining metabolic profiling of cancer cells under ER stress conditions were selected, with a focus on identifying potential biomarkers and therapeutic targets. Results: Metabolomic studies highlight significant shifts in lipid metabolism, protein synthesis, and oxidative stress management in response to ER stress. These metabolic alterations are crucial for tumor adaptation and survival. Additionally, targeting ER stress-related metabolic pathways has shown potential in preclinical models, suggesting new therapeutic strategies. Conclusions: Understanding the metabolic impact of ER stress in cancer provides valuable opportunities for drug development. Metabolomics-based approaches may help identify novel biomarkers and therapeutic targets, enhancing the effectiveness of antitumor therapies.
    Keywords:  biochemical pathways; cancer; drug discovery; endoplasmic reticulum stress; metabolomics; tumor microenvironment; unfolded protein response
    DOI:  https://doi.org/10.3390/metabo15040221
  32. Anal Chem. 2025 Apr 21.
      Caenorhabditis elegans is a widely used genetic model organism; however, the worm cuticle complicates extraction of intracellular proteins, a prerequisite for typical bottom-up proteomics. Conventional physical disruption procedures are not only time-consuming but can also cause significant sample loss, making it difficult to perform proteomics with low-input samples. Here, for the first time, we present an on-filter in-cell (OFIC) processing approach that can digest C. elegans proteins directly in the cells of the organism after methanol fixation. With OFIC processing and single-shot LC-MS analysis, we identified over 9400 proteins from a sample of only 200 worms, the largest C. elegans proteome reported to date that did not require fractionation or enrichment. We systematically evaluated the performance of the OFIC approach by comparing it to conventional lysis-based methods. Our data suggest superior performance of OFIC processing for C. elegans proteome identification and quantitation. We further evaluated the OFIC approach with even lower-input samples, including single worms. Then, we used this method to determine how the proteome is impacted by loss of superoxide dismutase sod-1, the ortholog of human SOD1, a gene associated with amyotrophic lateral sclerosis. Analysis of 8800 proteins from only 50 worms as the initial input showed that loss of sod-1 affects the abundance of proteins required for stress response, ribosome biogenesis, and metabolism. In conclusion, our streamlined OFIC approach, which can be broadly applied to other systems, minimizes sample loss while offering the simplest workflow reported to date for C. elegans proteomics.
    DOI:  https://doi.org/10.1021/acs.analchem.4c05003
  33. Cells. 2025 Apr 15. pii: 598. [Epub ahead of print]14(8):
      Tumor metabolism has emerged as a critical target in cancer therapy, revolutionizing our understanding of how cancer cells grow, survive, and respond to treatment. Historically, cancer research focused on genetic mutations driving tumorigenesis, but in recent decades, metabolic reprogramming has been recognized as a hallmark of cancer. The TP53 inducible glycolysis and apoptosis regulator, or TIGAR, affects a wide range of cellular and molecular processes and plays a key role in cancer cell metabolism by regulating the balance between glycolysis and antioxidant defense mechanisms. Cancer cells often exhibit a shift towards aerobic glycolysis (the Warburg effect), which allows rapid energy production and gives rise to biosynthetic intermediates for proliferation. By inhibiting glycolysis, TIGAR can reduce the proliferation rate of cancer cells, particularly in early-stage tumors or specific tissue types. This metabolic shift may limit the resources available for rapid cell division, thereby exerting a tumor-suppressive effect. However, this metabolic shift also leads to increased levels of reactive oxygen species (ROS), which can damage the cell if not properly managed. TIGAR helps protect cancer cells from excessive ROS by promoting the pentose phosphate pathway (PPP), which generates NADPH-a key molecule involved in antioxidant defense. Through its actions, TIGAR decreases the glycolytic flux while increasing the diversion of glucose-6-phosphate into the PPP. This reduces ROS levels and supports biosynthesis and cell survival by maintaining the balance of nucleotides and lipids. The role of TIGAR has been emerging as a prognostic and potential therapeutic target in different types of cancers. This review highlights the role of TIGAR in different types of cancer, evaluating its potential role as a diagnostic marker and a therapeutic target.
    Keywords:  P53; ROS; cancer metabolism; gastric cancer; ketogenic diet; pancreatic cancer; pentose phosphate pathway
    DOI:  https://doi.org/10.3390/cells14080598
  34. Acta Biochim Biophys Sin (Shanghai). 2025 Apr 23.
      Glutamine metabolism is a hallmark of cancer metabolism. This study aims to perform a comprehensive and systematic single-cell profile of glutamine metabolism in premalignant and malignant gastric lesions. We use single-cell transcriptomics data from chronic atrophic gastritis (CAG) and early gastric cancer (EGC) lesions and investigate glutamine metabolism features at the single-cell level. Experiments are implemented to validate the expression and biological role of ERO1LB in gastric cancer (GC). A single-cell atlas based on 22511 cells from premalignant and early-malignant gastric lesions is established. Among these cells, epithelial cells constitute the dominant cell population in both CAG and EGC lesions. The activity of glutamine metabolism is higher in epithelial cells from EGC lesions than in those from CAG lesions. Among the epithelial cell subpopulations, glutamine metabolism is more active in the epithelial cell subpopulation cluster_4 in EGCs than in CAG lesions. As a key marker gene of this subpopulation, ERO1LB is experimentally proven to be overexpressed in human GC tissue lesions. In both in vitro and in vivo experiments, overexpression of ERO1LB in GC cells increases glutamine metabolism, facilitates cell growth and migration and prevents cell apoptosis, and vice versa. This study provides insight into the cellular heterogeneityof glutamine metabolism within the gastric mucosa in premalignant and malignant gastric lesions and identifies ERO1LB as a key orchestrator of glutamine metabolism, which may help to identify markers for GC prevention and contribute to our understanding of GC pathogenesis.
    Keywords:  ERO1LB; cellular heterogeneity; chronic atrophic gastritis; gastric cancer; glutamine metabolism; single-cell transcriptomics
    DOI:  https://doi.org/10.3724/abbs.2025061
  35. Appl Microbiol Biotechnol. 2025 Apr 22. 109(1): 101
      The demand for sustainable and eco-friendly alternatives to fossil and plant oil-derived chemicals has spurred interest in microbial production of lipids, particularly triacylglycerols, fatty acids, and their derivatives. Yeasts are promising platforms for synthesizing these compounds due to their high lipid accumulation capabilities, robust growth, and generally recognized as safe (GRAS) status. There is vast interest in fatty acid and triacylglycerol products with tailored fatty acid chain lengths and compositions, such as polyunsaturated fatty acids and substitutes for cocoa butter and palm oil. However, microbes naturally produce a limited set of mostly long-chain fatty acids, necessitating the development of microbial cell factories with customized fatty acid profiles. This review explores the capabilities of key enzymes involved in fatty acid and triacylglycerol synthesis, including fatty acid synthases, desaturases, elongases, and acyltransferases. It discusses factors influencing fatty acid composition and presents engineering strategies to enhance fatty acid synthesis. Specifically, we highlight successful engineering approaches to modify fatty acid profiles in triacylglycerols and produce tailored fatty acids, and we offer recommendations for host selection to streamline engineering efforts. KEY POINTS: • Detailed overview on all basic aspects of fatty acid metabolism in yeast • Comprehensive description of fatty acid profile tailoring in yeast • Extensive summary of applying tailored fatty acid profiles in production processes.
    Keywords:  Cell factory; Fatty acid; Lipid; Metabolic engineering; Renewable resources; Yeast
    DOI:  https://doi.org/10.1007/s00253-025-13487-1