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However, robust detection of multiple biomolecule types from the same biological sample remains challenging. We developed a multi-omics platform for the simultaneous detection of metabolites (polar and semi-polar), lipids, proteins, and native peptides, all detected in a high-throughput manner from a single tube. As a proof-of-concept for the platform, we profiled the profound and dynamic molecular changes occurring in tomato during fruit development. This included optimizing sample collection, standardizing data acquisition from the chromatographic systems, and developing a bioinformatic pipeline to integrate data from the diverse omics technologies. Across omics layers, we detected thousands of biomolecules whose abundances shifted significantly during fruit development in peel and flesh tissues, providing temporal signatures that differentiate fruit developmental stages. This includes the characterization of numerous naturally produced endogenous peptides that exhibit dynamic changes in composition and cleavage preferences. Finally, we demonstrate the use of a machine learning framework for unsupervised integration of this type of high-throughput data. Collectively, our multi-omics platform enables a comprehensive exploration of diverse biological tissues and biofluids with broad applicability across research fields.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c03036","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T21:01:37Z","timestamp":1789419697000},"page":"28106-28121","source":"Crossref","is-referenced-by-count":0,"title":["Single-Tube\nMass Spectrometry-Based Workflow for Multi-Omics\nProfiling of Diverse Biomolecules"],"prefix":"10.1021","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1348-2814","authenticated-orcid":true,"given":"Maxim","family":"Itkin","sequence":"first","affiliation":[{"name":"Weizmann Institute of Science , , ,","place":["Rehovot, Israel, 7610001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5226-7554","authenticated-orcid":true,"given":"Bareket","family":"Dassa","sequence":"additional","affiliation":[{"name":"Weizmann Institute of Science , , ,","place":["Rehovot, Israel, 7610001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7279-0246","authenticated-orcid":true,"given":"Yishai","family":"Levin","sequence":"additional","affiliation":[{"name":"Weizmann Institute of Science , , ,","place":["Rehovot, Israel, 7610001"]},{"name":"Weizmann Institute of Science , , ,","place":["Rehovot, Israel, 7610001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrii","family":"Vainer","sequence":"additional","affiliation":[{"name":"Weizmann Institute of Science , , ,","place":["Rehovot, Israel, 7610001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asaph","family":"Aharoni","sequence":"additional","affiliation":[{"name":"Weizmann Institute of Science , , ,","place":["Rehovot, Israel, 7610001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4619-7219","authenticated-orcid":true,"given":"Sergey","family":"Malitsky","sequence":"additional","affiliation":[{"name":"Weizmann Institute of Science , , ,","place":["Rehovot, Israel, 7610001"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"2026092909102014300_cit1","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1038\/s41592-021-01197-1","article-title":"Mass spectrometry-based\nmetabolomics: a guide for annotation, quantification and best reporting\npractices","volume":"18","author":"Alseekh","year":"2021","journal-title":"Nat. Methods"},{"key":"2026092909102014300_cit2","doi-asserted-by":"publisher","DOI":"10.1186\/s13007-016-0146-2","article-title":"Protocol:\na fast, comprehensive and reproducible one-step extraction method\nfor the rapid preparation of polar and semi-polar metabolites, lipids,\nproteins, starch and cell wall polymers from a single sample","volume":"12","author":"Salem","year":"2016","journal-title":"Plant Methods"},{"key":"2026092909102014300_cit3","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.635971","article-title":"Three-in-One\nSimultaneous Extraction of Proteins, Metabolites and Lipids for Multi-Omics","volume":"12","author":"Kang","year":"2021","journal-title":"Front. Genet."},{"key":"2026092909102014300_cit4","doi-asserted-by":"publisher","first-page":"3188","DOI":"10.7150\/thno.80435","article-title":"Integration\nof Metabolomics and Peptidomics\nReveals Distinct Molecular Landscape of Human Diabetic Kidney Disease","volume":"13","author":"Jiang","year":"2023","journal-title":"Theranostics"},{"key":"2026092909102014300_cit5","doi-asserted-by":"publisher","first-page":"4217","DOI":"10.1021\/acs.analchem.0c04764","article-title":"Multi-Omic Single-Shot\nTechnology for Integrated Proteome and Lipidome Analysis","volume":"93","author":"He","year":"2021","journal-title":"Anal. Chem."},{"key":"2026092909102014300_cit6","doi-asserted-by":"publisher","first-page":"10930","DOI":"10.1021\/acs.analchem.3c00734","article-title":"Mass Spectrometry-Based Multi-omics\nIntegration with a Single Set of C. elegans Samples","volume":"95","author":"Zhu","year":"2023","journal-title":"Anal. Chem."},{"key":"2026092909102014300_cit7","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1021\/acs.analchem.2c02042","article-title":"Rapid Multi-Omics\nSample Preparation\nfor Mass Spectrometry","volume":"95","author":"Muehlbauer","year":"2023","journal-title":"Anal. Chem."},{"key":"2026092909102014300_cit8","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1021\/acs.analchem.5b04491","article-title":"Toward merging untargeted\nand targeted methods in mass spectrometry-based\nmetabolomics and lipidomics","volume":"88","author":"Cajka","year":"2016","journal-title":"Anal. 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Lipid Res."},{"key":"2026092909102014300_cit19","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1111\/nph.13852","article-title":"Viral infection of\nthe marine alga Emiliania huxleyi triggers lipidome remodeling and\ninduces the production of highly saturated triacylglycerol","volume":"210","author":"Malitsky","year":"2016","journal-title":"New Phytol."},{"key":"2026092909102014300_cit20","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7001","article-title":"Fumarate induces redox-dependent senescence by modifying\nglutathione metabolism","volume":"6","author":"Zheng","year":"2015","journal-title":"Nat. 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Lipid\nRes."},{"key":"2026092909102014300_cit28","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1104\/pp.105.1.405","article-title":"Carotenoid\nBiosynthesis during Tomato Fruit Development (Evidence for Tissue-Specific\nGene Expression)","volume":"105","author":"Fraser","year":"1994","journal-title":"Plant Physiol."},{"key":"2026092909102014300_cit29","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2229-14-29","article-title":"Genome-wide Data (ChIP-seq) Enabled\nIdentification of Cell Wall-Related and Aquaporin Genes as Targets\nof Tomato ASR1, a Drought Stress-Responsive Transcription Factor","volume":"14","author":"Ricardi","year":"2014","journal-title":"BMC Plant Biol."},{"key":"2026092909102014300_cit30","doi-asserted-by":"publisher","first-page":"6490","DOI":"10.1093\/jxb\/erab269","article-title":"Multiomics\nAnalyses Reveal the Roles of the ASR1 Transcription Factor during\nTomato Fruits","volume":"72","author":"Domi\u0301nguez","year":"2021","journal-title":"J. Exp. Bot."},{"key":"2026092909102014300_cit31","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1104\/pp.97.1.80","article-title":"Molecular Cloning of Tomato Pectin\nMethylesterase Gene and Its Expression in Rutgers, Ripening Inhibitor,\nand Nonripening, and Never Ripe Tomato Fruits","volume":"97","author":"Harriman","year":"1991","journal-title":"Plant Physiol."},{"key":"2026092909102014300_cit32","doi-asserted-by":"publisher","DOI":"10.3389\/fpls.2020.00238","article-title":"Characterization of\nthe Tomato (Solanum lycopersicum) Pectin\nMethylesterases: Evolution, Activity of Isoforms and Expression during\nFruit Ripening","volume":"11","author":"Wen","year":"2020","journal-title":"Front. Plant Sci."},{"key":"2026092909102014300_cit33","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1104\/pp.106.2.429","article-title":"Reduction in Pectin\nMethylesterase Activity Modifies\nTissue Integrity and Cation Levels in Ripening Tomato (Lycopersicon esculentum Mill.) Fruits","volume":"106","author":"Tieman","year":"1994","journal-title":"Plant Physiol."}],"container-title":["Analytical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.analchem.6c03036","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/38\/28106\/68505771\/acs.analchem.6c03036.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/98\/38\/28106\/68505771\/acs.analchem.6c03036.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:22:23Z","timestamp":1790688143000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancham\/article\/98\/38\/28106\/5429676\/Single-Tube-Mass-Spectrometry-Based-Workflow-for"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":33,"journal-issue":{"issue":"38","published-online":{"date-parts":[[2026,9,14]]},"published-print":{"date-parts":[[2026,9,29]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.analchem.6c03036","relation":{},"ISSN":["0003-2700","1520-6882"],"issn-type":[{"value":"0003-2700","type":"print"},{"value":"1520-6882","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]}}}