{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:10:47Z","timestamp":1789056647544,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871095"],"award-info":[{"award-number":["81871095"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32300794"],"award-info":[{"award-number":["32300794"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cachexia is a wasting syndrome associated with imbalanced energy metabolism and loss of adipose and muscle tissues and contributes to morbidity and mortality in ageing as well as in patients with severe chronic diseases, including cancer. At present, there are no treatments addressing cachexia that have reached validation to be used in the clinic. In this study, we investigate the protective role of SIRT6, an important regulator of energy homeostasis and health preservation, against Lewis lung carcinoma (LLC)\u2013induced cachexia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      SIRT6 levels of serum from gastric cancer patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200922, 65.27\u2009\u00b1\u200912.50\u2009years old, 40.9% females) and healthy controls (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200922, 63.50\u2009\u00b1\u200910.77\u2009years old, 45.4% females) were measured to evaluate the correlation between circulating SIRT6 levels and cancer cachexia development. Ten\u2010week\u2010old SIRT6 transgenic (TG) and wild type (WT) male mice injected with LLC cells (1.5\u2009\u00d7\u200910\n                      <jats:sup>6<\/jats:sup>\n                      per mouse) were used to investigate the protective effects of SIRT6 on cachexia\u2010associated adipose browning and lipolysis and the underlying mechanisms. We explored the effect of SIRT6 on LLC\u2010conditioned medium induced lipolysis in mature adipocytes, differentiated from primary mouse embryonic fibroblasts (MEFs). We evaluated the in\u00a0vitro effect of a SIRT6 activator by treatment of MDL800.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SIRT6 concentrations were significantly higher in non\u2010cachectic cancer patients (3.41\u2009\u00b1\u20090.30\u2009ng\/mL) compared to cachectic cancer patients (3.20\u2009\u00b1\u20090.23\u2009ng\/mL,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), suggesting the negative correlation between SIRT6 level and cachexia in patients with cancer. SIRT6 overexpression significantly ameliorated tumour\u2010induced wasting and energy expenditure in white adipose tissues (eWAT mass loss: 66% in WT vs. 32% in TG; iWAT mass loss: 69% in WT vs. 40% in TG) through suppression of browning and lipolysis. In LLC\u2010induced cachexia, tumour necrosis factor\u2010\u03b1 receptor 2 (TNFR2) mediated the inhibition of SIRT6 on lipolytic signalling, because the difference in lipolysis between the WT and SIRT6 knockout group was almost eliminated by TNFR2 neutralizing antibody. Increased serum TNFR2 concentration was found in cachectic cancer patients (690.41\u2009pg\/mL in non\u2010cachectic vs. 1166.98\u2009pg\/mL in cachectic patients,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). A selective SIRT6 pharmaceutical activator, MDL800, could completely reverse LLC\u2010induced lipolysis in adipocytes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We found an unexpected beneficial function of SIRT6 in cancer cachexia, demonstrating that increased SIRT6 expression or activity is capable of protecting the host against cachexia\u2010associated tissue wasting, providing a concept of future therapies for cachexia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13734","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T22:05:51Z","timestamp":1740002751000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["SIRT6 Ameliorates Cancer Cachexia\u2013Associated Adipose Wasting by Suppressing TNFR2 Signalling in Mice"],"prefix":"10.1002","volume":"16","author":[{"given":"Kang","family":"Xu","sequence":"first","affiliation":[{"name":"Protein Science Key Laboratory of the Ministry of Education, School of Pharmaceutical Sciences Tsinghua University  Beijing China"},{"name":"School of Basic Medical Sciences Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yida","family":"Wang","sequence":"additional","affiliation":[{"name":"Protein Science Key Laboratory of the Ministry of Education, School of Pharmaceutical Sciences Tsinghua University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Nutrition and Department of Health Medicine, Peking Union Medical College Hospital Chinese Academy of Medical Sciences  Beijing 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