{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:51:24Z","timestamp":1791265884446,"version":"4.1.0"},"reference-count":180,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cancer stem cells (CSCs) are increasingly recognized as metabolically plastic subpopulations within malignant tissues that drive tumor initiation, metastatic dissemination, and relapse after therapy. Although traditional models of cancer metabolism have emphasized aerobic glycolysis, CSCs rarely exhibit a single, clearly defined bioenergetic phenotype. Rather, they dynamically remodel glucose utilization, oxidative phosphorylation, redox regulation, de novo fatty acid synthesis, lipid uptake, lipid sequestration, and fatty acid oxidation in response to hypoxic conditions, nutrient restriction, stromal interactions, and therapeutic perturbations. This review focuses on two interconnected aspects of metabolic flexibility: lipid flux and mitochondrial plasticity. We examine how de novo lipogenesis, CD36\u2010mediated fatty acid uptake, fatty acid\u2010binding protein trafficking, cholesterol biosynthesis, and lipid\u2010droplet turnover contribute to stemness, membrane remodeling, metastatic potential, and resistance to cytotoxic agents. We also examine how mitochondrial dynamics, including fusion, fission, mitophagy, and biogenesis, together with reactive oxygen species buffering and shifts in oxidative phosphorylation, facilitate CSC survival during chemotherapy, radiotherapy, targeted therapy, and immune\u2010mediated cytotoxicity. Particular emphasis is placed on the integration of fatty acid oxidation to respiratory metabolism, on the epigenetic consequences associated with the acetyl\u2010CoA availability, and the metabolic crosstalk linking CSCs to adipocytes, fibroblasts, mesenchymal cells, and immune cell populations in the tumor microenvironment. Finally, we evaluate therapeutic strategies involving inhibitors of fatty acid synthase (FASN), acetyl\u2010CoA carboxylase (ACC), stearoyl\u2010CoA desaturase\u20101 (SCD1), carnitine palmitoyltransferase\u20101 (CPT1), and OXPHOS. We also discuss combination therapies, nanotechnology\u2010based drug delivery, and emerging artificial intelligence (AI)\u2010guided approaches. Taken together, current evidence identifies the lipid\u2013mitochondrial axis as a critical systems\u2010level driver of therapeutic resistance and a promising target for improving long\u2010term cancer control.<\/jats:p>","DOI":"10.1002\/cam4.72275","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T05:31:07Z","timestamp":1789795867000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Reprogramming of Cancer Stem Cells: Targeting Lipid Flux and Mitochondrial Plasticity to Overcome Therapeutic Resistance"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1129-1785","authenticated-orcid":false,"given":"Daniel Ejim","family":"Uti","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Basic Medical Sciences, College of Medicine Federal University of Health Sciences  Otukpo Benue State Nigeria"},{"name":"Department of Biochemistry, Research and Publications Kampala International University  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4105-8615","authenticated-orcid":false,"given":"Esther Ugo","family":"Alum","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Research and Publications Kampala International University  Kampala Uganda"},{"name":"Department of Biochemistry, Faculty of Science Ebonyi State University  Abakaliki Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7280-0889","authenticated-orcid":false,"given":"Josephine E.","family":"Egbung","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, Faculty of Allied Health Sciences University of Calabar  Calabar Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuhair 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