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Exploring these cancer-specific metabolic alterations offers potential selective therapeutic strategies. However, targeting a single essential gene in cancer treatment often faces challenges, including resistance, lack of targetable oncogenes, and potential harm to non-tumor cells. Targeting multiple genes has been proposed as a solution to overcome these issues, e.g., a synthetic lethal (SL) set, defined as a minimal combination of non-lethal genetic perturbations that lead to cell death. This study theoretically examined the potential of SL sets to identify selective drug targets across 13 cancer types and the corresponding non-tumor tissues, utilizing context-specific genome-scale metabolic models. To ensure the minimization of therapeutic side effects, this work introduced the concept of\n                    <jats:italic>strictly-selective<\/jats:italic>\n                    drug targets (SSDTs) and the lack of harmful effects of the identified targets in all 13 different non-tumor tissues was meticulously verified. Accordingly, for 13 types of cancers, over 500 SSDTs were identified, predominantly including higher-order SL sets with more than two targets in each set. Interestingly, for specific cancers where single essential or SL genes could not provide viable therapeutic solutions, SSDTs were provided by higher-order SL sets. Thus, for the first time, this study demonstrates that leveraging higher-order SL sets may offer promising strictly selective therapeutic solutions. Furthermore, nine quadruple SSDTs were identified, which commonly target five different cancers without harming any of the 13 non-tumor tissues. Further experimental validation of these findings is essential to identify the most promising treatment candidates for future clinical studies\/applications.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0342199","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:43:43Z","timestamp":1776275023000},"page":"e0342199","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Higher order synthetic lethals are keys to minimize cancer treatment effects on non-tumor cells"],"prefix":"10.1371","volume":"21","author":[{"given":"Mehdi","family":"Dehghan 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Warburg","year":"1924","journal-title":"Naturwissenschaften"},{"issue":"2","key":"pone.0342199.ref002","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrc2981","article-title":"Regulation of cancer cell metabolism","volume":"11","author":"RA Cairns","year":"2011","journal-title":"Nat Rev Cancer"},{"key":"pone.0342199.ref003","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1146\/annurev-cellbio-092910-154237","article-title":"Aerobic glycolysis: meeting the metabolic requirements of cell proliferation","volume":"27","author":"SY Lunt","year":"2011","journal-title":"Annual Review of Cell and Developmental Biology"},{"issue":"5","key":"pone.0342199.ref004","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/BF01116556","article-title":"The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells","volume":"5","author":"EA Newsholme","year":"1985","journal-title":"Biosci 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Ngoi","year":"2025","journal-title":"Nat Rev Clin Oncol"},{"issue":"7363","key":"pone.0342199.ref044","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nature10363","article-title":"Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase","volume":"477","author":"C Frezza","year":"2011","journal-title":"Nature"},{"issue":"14","key":"pone.0342199.ref045","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1093\/bioinformatics\/btv134","article-title":"Logical transformation of genome-scale metabolic models for gene level applications and analysis","volume":"31","author":"C Zhang","year":"2015","journal-title":"Bioinformatics"},{"issue":"3","key":"pone.0342199.ref046","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1002\/msb.145122","article-title":"Identification of anticancer drugs for hepatocellular carcinoma through personalized genome-scale metabolic modeling","volume":"10","author":"R Agren","year":"2014","journal-title":"Mol Syst Biol"},{"issue":"1","key":"pone.0342199.ref047","doi-asserted-by":"crossref","first-page":"9058","DOI":"10.1038\/s41467-024-52900-7","article-title":"Benchmarking machine learning methods for synthetic lethality prediction in cancer","volume":"15","author":"Y Feng","year":"2024","journal-title":"Nat Commun"},{"issue":"8","key":"pone.0342199.ref048","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1038\/s41592-025-02772-6","article-title":"Deep-learning-based gene perturbation effect prediction does not yet outperform simple linear baselines","volume":"22","author":"C Ahlmann-Eltze","year":"2025","journal-title":"Nat Methods"},{"key":"pone.0342199.ref049","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11306-016-1051-4","article-title":"Recon 2.2: from reconstruction to model of human metabolism","volume":"12","author":"N Swainston","year":"2016","journal-title":"Metabolomics"},{"issue":"22","key":"pone.0342199.ref050","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.1093\/bioinformatics\/btv377","article-title":"Alternative preprocessing of RNA-Sequencing data in The Cancer Genome Atlas leads to improved analysis results","volume":"31","author":"M Rahman","year":"2015","journal-title":"Bioinformatics"},{"issue":"3","key":"pone.0342199.ref051","article-title":"A Systematic Evaluation of Methods for Tailoring Genome-Scale Metabolic Models","volume":"4","author":"S Opdam","year":"2017","journal-title":"Cell Syst"},{"issue":"4","key":"pone.0342199.ref052","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1003580","article-title":"Systematic evaluation of methods for integration of transcriptomic data into constraint-based models of metabolism","volume":"10","author":"D Machado","year":"2014","journal-title":"PLoS Comput 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Pratapa","year":"2015","journal-title":"Bioinformatics"},{"key":"pone.0342199.ref056","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: a major update to the DrugBank database for 2018","volume":"46","author":"DS Wishart","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pone.0342199.ref057","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkx247","article-title":"GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses","volume":"45","author":"Z Tang","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pone.0342199.ref058","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkac972","article-title":"The International Mouse Phenotyping Consortium: comprehensive knockout phenotyping underpinning the study of human disease","volume":"51","author":"T Groza","year":"2023","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pone.0342199.ref059","doi-asserted-by":"crossref","first-page":"2910","DOI":"10.18632\/oncotarget.6272","article-title":"Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation","volume":"7","author":"G De Preter","year":"2016","journal-title":"Oncotarget"},{"issue":"8","key":"pone.0342199.ref060","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.tibs.2014.06.005","article-title":"The pentose phosphate pathway and cancer","volume":"39","author":"KC Patra","year":"2014","journal-title":"Trends Biochem Sci"},{"issue":"9","key":"pone.0342199.ref061","first-page":"4923","article-title":"SiRNA targeting PFK1 inhibits proliferation and migration and enhances radiosensitivity by suppressing glycolysis in colorectal cancer","volume":"12","author":"R-F Tian","year":"2020","journal-title":"Am J Transl Res"},{"issue":"2","key":"pone.0342199.ref062","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/s41419-020-2278-6","article-title":"A20 targets PFKL and glycolysis to inhibit the progression of hepatocellular carcinoma","volume":"11","author":"Y Feng","year":"2020","journal-title":"Cell Death Dis"},{"key":"pone.0342199.ref063","doi-asserted-by":"crossref","first-page":"677860","DOI":"10.3389\/fcell.2021.677860","article-title":"Inhibition of miR-185-3p Confers Erlotinib Resistance Through Upregulation of PFKL\/MET in Lung Cancers","volume":"9","author":"K Li","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"7","key":"pone.0342199.ref064","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.molmed.2011.01.014","article-title":"Oxidative stress, inflammation and carcinogenesis are controlled through the pentose phosphate pathway by transaldolase","volume":"17","author":"A Perl","year":"2011","journal-title":"Trends Mol 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Sarfraz","year":"2020","journal-title":"Biofactors"},{"issue":"2","key":"pone.0342199.ref071","first-page":"85","article-title":"Oxidative Pentose Phosphate Pathway Enzyme 6-Phosphogluconate Dehydrogenase Plays a Key Role in Breast Cancer Metabolism","volume":"10","author":"IH Polat","year":"2021","journal-title":"Biology (Basel)"},{"issue":"9","key":"pone.0342199.ref072","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1007\/s12094-018-1833-4","article-title":"Inhibiting 6-phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation","volume":"20","author":"X Yang","year":"2018","journal-title":"Clin Transl Oncol"},{"key":"pone.0342199.ref073","doi-asserted-by":"crossref","first-page":"421","DOI":"10.3389\/fphar.2017.00421","article-title":"Inhibition of 6-phosphogluconate Dehydrogenase Reverses Cisplatin Resistance in Ovarian and Lung Cancer","volume":"8","author":"W Zheng","year":"2017","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0342199.ref074","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3390\/metabo13010034","article-title":"Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer","volume":"13","author":"GB Khan","year":"2022","journal-title":"Metabolites"},{"issue":"1","key":"pone.0342199.ref075","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/s41467-019-08921-8","article-title":"Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance","volume":"10","author":"R Liu","year":"2019","journal-title":"Nat Commun"},{"key":"pone.0342199.ref076","doi-asserted-by":"crossref","first-page":"15330338231190737","DOI":"10.1177\/15330338231190737","article-title":"Inhibition of 6-Phosphogluconate Dehydrogenase Reverses Epirubicin Resistance Through Metabolic Reprograming in Triple-Negative Breast Cancer Cells","volume":"22","author":"J Xu","year":"2023","journal-title":"Technol Cancer Res Treat"},{"issue":"4","key":"pone.0342199.ref077","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.bbrc.2018.03.079","article-title":"Inhibiting 6-phosphogluconate dehydrogenase reverses doxorubicin resistance in anaplastic thyroid cancer via inhibiting NADPH-dependent metabolic reprogramming","volume":"498","author":"L Ma","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"issue":"23","key":"pone.0342199.ref078","doi-asserted-by":"crossref","first-page":"6051","DOI":"10.3390\/ijms20236051","article-title":"Colon Cancer and Perturbations of the Sphingolipid Metabolism","volume":"20","author":"M Machala","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0342199.ref079","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nrc.2017.96","article-title":"Sphingolipid metabolism in cancer signalling and therapy","volume":"18","author":"B Ogretmen","year":"2018","journal-title":"Nat Rev Cancer"},{"issue":"2","key":"pone.0342199.ref080","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1158\/1535-7163.MCT-05-0420","article-title":"Sphingolipid targets in cancer therapy","volume":"5","author":"DE Modrak","year":"2006","journal-title":"Mol Cancer Ther"},{"key":"pone.0342199.ref081","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/bs.acr.2018.04.016","article-title":"Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era","volume":"140","author":"J Shaw","year":"2018","journal-title":"Adv Cancer Res"},{"issue":"8","key":"pone.0342199.ref082","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1016\/j.bbalip.2013.12.013","article-title":"Evolving concepts in cancer therapy through targeting sphingolipid metabolism","volume":"1841","author":"J-P Truman","year":"2014","journal-title":"Biochim Biophys Acta"},{"issue":"9","key":"pone.0342199.ref083","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.3390\/cancers14092183","article-title":"Targeting Sphingolipid Metabolism as a Therapeutic Strategy in Cancer Treatment","volume":"14","author":"AH Janneh","year":"2022","journal-title":"Cancers (Basel)"},{"key":"pone.0342199.ref084","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/2052-8426-2-15","article-title":"Role of solute carriers in response to anticancer drugs","volume":"2","author":"Q Li","year":"2014","journal-title":"Mol Cell Ther"},{"issue":"2","key":"pone.0342199.ref085","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s13402-022-00749-7","article-title":"Nucleotide sugar transporter SLC35A2 is involved in promoting hepatocellular carcinoma metastasis by regulating cellular glycosylation","volume":"46","author":"H Cheng","year":"2023","journal-title":"Cell Oncol (Dordr)"},{"key":"pone.0342199.ref086","doi-asserted-by":"crossref","first-page":"1155182","DOI":"10.3389\/fimmu.2023.1155182","article-title":"Comprehensive analysis of 33 human cancers reveals clinical implications and immunotherapeutic value of the solute carrier family 35 member A2","volume":"14","author":"S Xu","year":"2023","journal-title":"Front Immunol"},{"key":"pone.0342199.ref087","doi-asserted-by":"crossref","first-page":"6827","DOI":"10.2147\/OTT.S177639","article-title":"Cytidine monophosphate N-acetylneuraminic acid synthetase enhances invasion of human triple-negative breast cancer cells","volume":"11","author":"EM O\u2019Day","year":"2018","journal-title":"Onco Targets Ther"},{"issue":"11","key":"pone.0342199.ref088","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.21873\/anticanres.13842","article-title":"N-acetylgalactosamine-6-sulfatase (GALNS), Similar to Glycodelin, Is a Potential General Biomarker for Multiple Malignancies","volume":"39","author":"M-L Ho","year":"2019","journal-title":"Anticancer Res"},{"key":"pone.0342199.ref089","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12935-020-1106-5","article-title":"Circular RNA ATXN7 promotes the development of gastric cancer through sponging miR-4319 and regulating ENTPD4","volume":"20","author":"Z Zhang","year":"2020","journal-title":"Cancer Cell Int"},{"issue":"14","key":"pone.0342199.ref090","doi-asserted-by":"crossref","first-page":"11488","DOI":"10.1021\/acs.jmedchem.4c00113","article-title":"New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives","volume":"67","author":"V Previtali","year":"2024","journal-title":"J Med Chem"},{"issue":"6166","key":"pone.0342199.ref091","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1126\/science.1247005","article-title":"Genome-scale CRISPR-Cas9 knockout screening in human cells","volume":"343","author":"O Shalem","year":"2014","journal-title":"Science"},{"issue":"8","key":"pone.0342199.ref092","first-page":"671","article-title":"Orthologous CRISPR\u2013Cas9 enzymes for combinatorial genetic screens","volume":"15","author":"FJ Najm","year":"2018","journal-title":"Nature Methods"},{"issue":"5","key":"pone.0342199.ref093","first-page":"2079","article-title":"Design and analysis of genome-wide pooled shRNA screens","volume":"9","author":"M Kampmann","year":"2014","journal-title":"Cell Reports"},{"issue":"1","key":"pone.0342199.ref094","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrd3010","article-title":"Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application","volume":"9","author":"AL Jackson","year":"2010","journal-title":"Nat Rev Drug Discov"},{"issue":"11","key":"pone.0342199.ref095","first-page":"674","article-title":"Genomic screening with RNAi: results and challenges","volume":"15","author":"S Mohr","year":"2014","journal-title":"Nature Reviews Molecular Cell Biology"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0342199","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:43:54Z","timestamp":1776275034000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0342199"}},"subtitle":[],"editor":[{"given":"Bashir 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