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Recent studies have indicated that cardiac atrophy may play an important role in DOX\u2010induced cardiotoxicity. However, the mechanisms responsible for DOX\u2010induced cardiac and skeletal muscle atrophy remain unclear. 6\u2010Shogaol (6\u2010SH) is a bioactive component from ginger, which exhibits various bioactive effects and can alleviate cisplatin\u2010induced cachexia. In this work, we systematically assessed the effects of DOX and\/or 6\u2010SH on heart and skeletal muscle, as well as the underlying mechanisms. C57BL\/6 mice were treated with DOX (5\u2009mg\/kg\/3d, 4 doses, intraperitoneal) and given high or low doses of 6\u2010SH (10\/2.5\u2009mg\/kg, qd, intraperitoneal) for 14\u2009days. Body weight, skeletal muscle mass, heart mass, grip strength, food intake and cardiac function were significantly reduced in DOX\u2010treated mice, with these impairments notably ameliorated by 6\u2010SH. Unexpectedly, 6\u2010SH synergistically enhanced the antitumor efficacy of DOX. The DOX\u2010induced significant decline in mitochondrial levels and slow\u2010to\u2010fast fiber type shift in skeletal muscle were notably attenuated by 6\u2010SH treatment. Meanwhile, 6\u2010SH exerted a protective effect against DOX\u2010induced increases in cardiac oxidative stress, cardiac injury markers and inflammatory cytokines. DOX significantly upregulated the E3 ubiquitin ligases Atrogin1 and MuRF1 and downregulated MyoD and MyoG in the heart and skeletal muscle. Furthermore, DOX activated necroptosis, as evidenced by increased phosphorylation of receptor\u2010interacting protein kinase (RIPK) 1, RIPK3, and mixed\u2010lineage kinase domain\u2010like (MLKL). 6\u2010SH negatively regulated E3 ubiquitin ligases and necroptosis, while upregulating myogenic regulatory factors. In conclusion, 6\u2010SH attenuated DOX\u2010induced cardiac atrophy, skeletal muscle atrophy and cardiotoxicity by inhibiting E3 ubiquitin ligases and necroptosis.<\/jats:p>","DOI":"10.1002\/ptr.70276","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:25:55Z","timestamp":1773757555000},"page":"3132-3149","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["6\u2010Shogaol Attenuates Doxorubicin\u2010Induced Cardiac and Skeletal Muscle Atrophy by Inhibiting\n                    <scp>E3<\/scp>\n                    Ubiquitin Ligases and Necroptosis"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0101-5039","authenticated-orcid":false,"given":"Xipeng","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"School of Pharmacy Shanghai University of Traditional Chinese Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanjun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Xin","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0762-8496","authenticated-orcid":false,"given":"Cheng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.177027"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13265"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph14060571"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0301379"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.812578"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010021\u201003614\u2010x"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2013.05.016"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph13120450"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9030263"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/fsn3.4129"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/Jco.2007.14.9401"},{"key":"e_1_2_11_13_1","unstructured":"Guo C. 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