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Increased lactate production, either due to the Warburg effect from tumors or accelerated glycolysis effects from cachectic muscle, is the most dangerous factor for cancer cachexia. This study aimed to explore the efficiency of 2-deoxy-D-glucose (2-DG) in blocking Cori cycle activity and its therapeutic effect on cachexia-associated muscle wasting. A C26 adenocarcinoma xenograft model was used to study cancer cachectic metabolic derangements. Tumor-free lean mass, hindlimb muscle morphology, and fiber-type composition were measured after in vivo 2-DG administration. Activation of the ubiquitin-dependent proteasome pathway (UPS) and autophagic\u2013lysosomal pathway (ALP) was further assessed. The cachectic skeletal muscles of tumor-bearing mice exhibited altered glucose and lipid metabolism, decreased carbohydrate utilization, and increased lipid \u03b2-oxidation. Significantly increased gluconeogenesis and decreased ketogenesis were observed in cachectic mouse livers. 2-DG significantly ameliorated cancer cachexia-associated muscle wasting and decreased cachectic-associated lean mass levels and fiber cross-sectional areas. 2-DG inhibited protein degradation-associated UPS and ALP, increased ketogenesis in the liver, and promoted ketone metabolism in skeletal muscle, thus enhancing mitochondrial bioenergetic capacity. 2-DG effectively prevents muscle wasting by increasing ATP synthesis efficiency via the ketone metabolic pathway and blocking the abnormal Cori cycle.<\/jats:p>","DOI":"10.3390\/cells11192987","type":"journal-article","created":{"date-parts":[[2022,9,25]],"date-time":"2022-09-25T21:14:28Z","timestamp":1664140468000},"page":"2987","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["2-Deoxy-D-glucose Alleviates Cancer Cachexia-Induced Muscle Wasting by Enhancing Ketone Metabolism and Inhibiting the Cori Cycle"],"prefix":"10.3390","volume":"11","author":[{"given":"Lulu","family":"Wei","sequence":"first","affiliation":[{"name":"Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranran","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9299-4716","authenticated-orcid":false,"given":"Junaid","family":"Wazir","sequence":"additional","affiliation":[{"name":"Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Lin","sequence":"additional","affiliation":[{"name":"Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Song","sequence":"additional","affiliation":[{"name":"Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyuan","family":"Pu","sequence":"additional","affiliation":[{"name":"Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8366-7887","authenticated-orcid":false,"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical School, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonglan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2868-5112","authenticated-orcid":false,"given":"Hongwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1470-2045(10)70218-7","article-title":"Definition and classification of cancer cachexia: An international consensus","volume":"12","author":"Fearon","year":"2011","journal-title":"Lancet 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