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Saikosaponin D (SSD), a major bioactive component of <jats:italic>Radix Bupleuri<\/jats:italic>, exhibits antiinflammatory, anti\u2010tumor, anti\u2010oxidant, anti\u2010viral, and hepatoprotective effects. In this study, we demonstrated that SSD is a promising agent for the treatment of cancer cachexia. SSD could alleviate TCM\u2010induced myotube atrophy and inhibit the expression of E3 ubiquitin ligases muscle RING\u2010finger containing protein\u20101 (MuRF1) and muscle atrophy Fbox protein (Atrogin\u20101\/MAFbx) in vitro. Moreover, SSD suppressed the progression of cancer cachexia, with significant improvements in the loss of body weight, gastrocnemius muscle, and tibialis anterior muscle mass in vivo. Mechanism investigations demonstrated that SSD could directly bind to STAT3 and specifically inhibit its phosphorylation as well as its transcriptional activity. Overexpression of STAT3 partially abolished the inhibitory effect of SSD on myotube atrophy, indicating that the therapeutic effect of SSD was attributed to STAT3 inhibition. These findings provide novel strategies for treatment of cancer cachexia by targeting STAT3, and SSD may be a promising drug candidate for cancer cachexia.<\/jats:p>","DOI":"10.1002\/ptr.7676","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T07:44:13Z","timestamp":1669794253000},"page":"809-819","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Saikosaponin D alleviates cancer cachexia by directly inhibiting <scp>STAT3<\/scp>"],"prefix":"10.1002","volume":"37","author":[{"given":"Lin\u2010lin","family":"Chen","sequence":"first","affiliation":[{"name":"School of Pharmacy Naval Medical University  Shanghai China"},{"name":"Department of Critical Care Medicine, School of Anesthesiology Naval Medical University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liu\u2010yuan","family":"Xia","sequence":"additional","affiliation":[{"name":"School of Pharmacy Naval Medical University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6778-6226","authenticated-orcid":false,"given":"Jun\u2010ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmacy Fujian University of Traditional Chinese Medicine  Fuzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Naval Medical University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2578-6524","authenticated-orcid":false,"given":"Jian\u2010yu","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Pharmacy Fujian University of Traditional Chinese Medicine  Fuzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Jiao Tong University Affiliated Sixth People's Hospital  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1264-0761","authenticated-orcid":false,"given":"Wei\u2010heng","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy Naval Medical University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.105"},{"key":"e_1_2_11_3_1","first-page":"E5266","article-title":"Specific targeting of TGF\u2010\u03b2 family ligands demonstrates distinct roles in the regulation of muscle mass in health and disease","volume":"114","author":"Chen J. 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