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This review analyzes the relationship between cancer and metabolic alterations, using the cosmological concepts of dark matter and dark energy to emphasize the often overlooked role of metabolism in tumor evolution. 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Guerrero 1,3,4, Ric Ryan H. Regalado 5, Jiayan Zhou 6, Kin Israel Notarte 7, Yu-Wei Lu 1, Paolo C. Encarnacion 1,3,4,8, Cidne Danielle D. Carles 3,4, Edrian M. Octavo 3, Dan Christopher I. Limbaroc 3,4, Charupong Saengboonmee 9 and Shih-Yi Huang 10, *  \nCitation: Chiu, C.-F.; Guerrero, J.J.G.; Regalado, R.R.H.; Zhou, J.; Notarte, K.I.; Lu, Y.-W.; Encarnacion, P.C.; Carles, C.D.D.; Octavo, E.M.; Limbaroc, D.C.I.; et al. Insights into Metabolic Reprogramming in Tumor Evolution and Therapy. Cancers 2024, 16, 3513. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers16203513  \nAcademic Editor: Daniel S. Sitar  \nReceived: 21 September 2024  \nRevised: 9 October 2024  \nAccepted: 15 October 2024  \nPublished: 17 October 2024  \nCorrected: 18 February 2025  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 110301, Taiwan; [jgguerrero1@up.edu.ph](jgguerrero1@up.edu.ph) (J.J.G.G.); [yuway120@gmail.com](yuway120@gmail.com) (Y.-W.L.); [pcencarnacion1@up.edu.ph](pcencarnacion1@up.edu.ph) (P.C.E.)  \n2 Taipei Medical University Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110301, Taiwan  \n3 College of Medicine, University of the Philippines Manila, Manila 1000, Philippines;  \n[cdcarles@up.edu.ph](cdcarles@up.edu.ph) (C.D.D.C.); [emoctavo@up.edu.ph](emoctavo@up.edu.ph) (E.M.O.); [dilimbaroc1@up.edu.ph](dilimbaroc1@up.edu.ph) (D.C.I.L.)  \n4 College of Public Health, University of the Philippines Manila, Manila 1000, Philippines  \n5 National Institute of Molecular Biology and Biotechnology, College of Science, University of the Philippines Diliman, Quezon City 1101, Philippines; [rhregalado@up.edu.ph](rhregalado@up.edu.ph)  \n6 Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; [jyzhou@stanford.edu](jyzhou@stanford.edu)  \n7 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; [kinotarte@gmail.com](kinotarte@gmail.com)  \n8 Department of Industrial Engineering and Management, Yuan Ze University, 135 Yuan-Tung Road, Chung-Li 32003, Taiwan  \n9 Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; [charusa@kku.ac.th](charusa@kku.ac.th)  \n10 School of Nutrition and Health Sciences, Taipei Medical University, Taipei 110301, Taiwan  \n* Correspondence: [chiucf@tmu.edu.tw](chiucf@tmu.edu.tw) (C.-F.C.); [sihuang@tmu.edu.tw](sihuang@tmu.edu.tw) (S.-Y.H.)  \nSimple Summary: Cancer is a global health problem caused by uncontrolled cell growth and changes in how cells get and use energy. This review compares cancer’s hidden metabolic changes to dark matter and dark energy in the universe, which are mysterious and often ignored. It looks at how cancer cells alter their energy use, such as through the Warburg effect and changes in fat and protein production, driven by genetic mutations. These changes help cancer grow and survive. The review suggests that targeting these metabolic pathways could be a new way to treat cancer. It calls for more research to better understand these changes and develop new therapies by focusing on the \"dark energy\" that fuels cancer cells.  \nAbstract: Background: Cancer remains a global health challenge, characterized not just by uncontrolled cell proliferation but also by the complex metabolic reprogramming that underlies its development and progression. Objectives: This review delves into the intricate relationship ","cbCaijJ2U2AAxNyb","https://ap.wps.com/l/cbCaijJ2U2AAxNyb","pdf",1560436,22,"English","# 1. Introduction\n## Cancer burden and prognosis\n## Metabolic reprogramming as a key driver\n# Background and objectives\n## Dark matter/dark energy analogy\n## Focus on overlooked metabolic roles\n# Methods and mechanistic focus\n## Warburg effect\n## Lipid synthesis, amino acid turnover, mitochondrial function\n# Results and therapeutic implications\n## Targeting metabolic pathways\n## Disrupting energy supply and signaling\n# Conclusions and outlook\n## Unveiling “dark energy” for future therapy","[{\"question\":\"What is the main focus of this review on cancer?\",\"answer\":\"It focuses on how complex metabolic reprogramming underlies cancer development and progression, emphasizing metabolic changes during tumor evolution and their therapeutic relevance.\"},{\"question\":\"Which metabolic mechanisms are highlighted as central in the review?\",\"answer\":\"The review scrutinizes the Warburg effect and related metabolic adaptations, including shifts in lipid synthesis, amino acid turnover, and mitochondrial function driven by key regulatory gene mutations.\"},{\"question\":\"How does the review propose metabolic pathways could be used in therapy?\",\"answer\":\"It suggests targeting cancer metabolic pathways to disrupt the tumor’s energy supply and signaling mechanisms, positioning metabolic reprogramming as a promising frontier for more effective treatments.\"}]","Insights into Metabolic Reprogramming in Tumor Evolution and Therapy - Review | PDF",1789983106,55]