{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T19:20:26Z","timestamp":1792264826099,"version":"4.4.0"},"reference-count":102,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>\n                    With the aim of identifying vulnerabilities of subpopulation\u2010specific metabolic networks, we used single\u2010cell transcriptomics to build mRNA\u2010based metabolic maps for 5512 cells from four proliferating cell populations (three liver cancer\u2010related and a control). Paradoxically, flux balance analysis (FBA) predicted no growth for any cell. Further analysis confirmed that this conclusion was not due to shared metabolites or insufficient mRNA sequencing depth. Instead, using our enzyme\u2010based\n                    <jats:italic>V<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    \u2010\n                    <jats:italic>constrained<\/jats:italic>\n                    model, FBA showed that each cell population should support biomass production for division, suggesting an enzyme\u2010stability based explanation of growth of individual cells, notwithstanding their apparent mRNA insufficiency. Comparing liver cancer cells and noncancerous liver cells via cell\u2010population\u2010average mRNA data, we identified cholesterol synthesis (SQLEr) and arginine synthesis as potential drug targets. Therefore, we suggest that identifying subclusters and their vulnerabilities reveals new drug targets for subpopulations, which should enable the reduction of drug resistance.\n                  <\/jats:p>","DOI":"10.1111\/febs.70680","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T07:18:34Z","timestamp":1786519114000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Metabolic\n                    <scp>mRNA<\/scp>\n                    insufficiency of single cells: Implications for drug targeting and resistance"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8282-7404","authenticated-orcid":false,"given":"Yanhua","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Endocrinology Sun Yat\u2010Sen Memorial Hospital, Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong\u2010Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center Sun Yat\u2010Sen Memorial Hospital, Sun Yat\u2010Sen University  Guangzhou China"},{"name":"Swammerdam Institute for Life Sciences University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0443-6114","authenticated-orcid":false,"given":"Hans V.","family":"Westerhoff","sequence":"additional","affiliation":[{"name":"Swammerdam Institute for Life Sciences University of Amsterdam  Amsterdam The Netherlands"},{"name":"Molecular Cell Biology, A\u2010Life, Faculty of Science, Amsterdam Institute for Molecules, Medicines and Systems Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"School of Biological Sciences, Faculty of Biology, Medicine and Health University of Manchester  Manchester UK"},{"name":"Stellenbosch Institute for Advanced Study (STIAS) Wallenberg Research Centre at Stellenbosch University  Stellenbosch South Africa"},{"name":"Department of Biochemistry Stellenbosch University  Stellenbosch South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/science.aaf2403","article-title":"Visualization and analysis of gene expression in tissue sections by spatial transcriptomics","volume":"353","author":"St\u00e5hl PL","year":"2016","journal-title":"Science"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.stem.2020.01.012","article-title":"The molecular anatomy of mouse skin during hair growth and rest","volume":"26","author":"Joost S","year":"2020","journal-title":"Cell Stem Cell"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1002\/ijc.25376","article-title":"Circulating mirnas are correlated with tumor 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