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Histone deacetylase (HDAC) inhibitors have been investigated for treating KRAS\u2010mutant lung cancer. In the current study, we investigate the effect of HDAC inhibitor (HDACi) belinostat at clinically relevant concentration on nuclear factor erythroid 2\u2010related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS\u2010mutant human lung cancer. LC\u2010MS metabolomic study of belinostat on mitochondrial metabolism was performed in G12C KRAS\u2010mutant H358 non\u2010small cell lung cancer cells. Furthermore, <jats:sc>l<\/jats:sc>\u2010methionine (methyl\u2010<jats:sup>13<\/jats:sup>C) isotope tracer was used to explore the effect of belinostat on one\u2010carbon metabolism. Bioinformatic analyses of metabolomic data were performed to identify the pattern of significantly regulated metabolites. To study the effect of belinostat on redox signaling ARE\u2010NRF2 pathway, luciferase reporter activity assay was done in stably transfected HepG2\u2010C8 cells (containing pARE\u2010TI\u2010luciferase construct), followed by qPCR analysis of NRF2 and its target gene in H358 cells, which was further confirmed in G12S KRAS\u2010mutant A549 cells. Metabolomic study reveals significantly altered metabolites related to redox homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate, and \u03b1\u2010ketoglutarate); urea cycle metabolites (Arginine, ornithine, argino\u2010succinate, aspartate, and fumarate); and antioxidative glutathione metabolism pathway (GSH\/GSSG and NAD\/NADH ratio) after belinostat treatment. <jats:sup>13<\/jats:sup>C stable isotope labeling data indicates potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. Moreover, belinostat downregulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anticancer effect of belinostat is mediated, potentially via Nrf2\u2010regulated glutathione pathway. Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS\u2010mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies.<\/jats:p>","DOI":"10.1002\/mc.23551","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T12:35:06Z","timestamp":1683290106000},"page":"1136-1146","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Histone deacetylase inhibitor belinostat regulates metabolic reprogramming in killing KRAS\u2010mutant human lung cancer cells"],"prefix":"10.1002","volume":"62","author":[{"given":"Rebecca M.","family":"Peter","sequence":"first","affiliation":[{"name":"Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey Piscataway New Jersey USA"},{"name":"Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey Piscataway New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Md. Shahid","family":"Sarwar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey Piscataway New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah Z.","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey Piscataway New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujue","family":"Wang","sequence":"additional","affiliation":[{"name":"Metabolomics Shared Resource Rutgers Cancer Institute of New Jersey New Brunswick New Jersey USA"},{"name":"Department of Medicine Rutgers\u2010Robert Wood Johnson Medical School New Brunswick New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyang","family":"Su","sequence":"additional","affiliation":[{"name":"Metabolomics Shared Resource Rutgers Cancer Institute of New Jersey New Brunswick New Jersey USA"},{"name":"Department of Medicine Rutgers\u2010Robert Wood Johnson Medical School New Brunswick New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9273-4217","authenticated-orcid":false,"given":"Ah\u2010Ng","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey Piscataway New Jersey 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