{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:09:06Z","timestamp":1792602546440,"version":"4.5.0"},"reference-count":138,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32130060"],"award-info":[{"award-number":["32130060"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82072160"],"award-info":[{"award-number":["82072160"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82401633"],"award-info":[{"award-number":["82401633"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["32130060"],"award-info":[{"award-number":["32130060"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82072160"],"award-info":[{"award-number":["82072160"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82401633"],"award-info":[{"award-number":["82401633"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Basic Research Program of Jiangsu","award":["BK20232023"],"award-info":[{"award-number":["BK20232023"]}]},{"name":"Universities of Jiangsu Province","award":["24KJA310007"],"award-info":[{"award-number":["24KJA310007"]}]},{"name":"Universities of Jiangsu Province","award":["24KJB310013"],"award-info":[{"award-number":["24KJB310013"]}]},{"name":"Nantong Science and Technology Program","award":["20241118084"],"award-info":[{"award-number":["20241118084"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Interleukin-6 (IL-6) is a cytokine with multiple biological effects. It plays a complex and seemingly paradoxical central role in both the physiological homeostasis and pathological processes of skeletal muscle. Under physiological conditions, particularly during acute exercise, IL-6 produced and secreted by the contracting skeletal muscle itself acts as an important \u201cmyokine.\u201d It operates in an autocrine, paracrine, or endocrine manner to regulate systemic energy metabolism, insulin sensitivity, muscle regeneration, and adaptive hypertrophy. This function is crucial for the health benefits conferred by exercise. However, under various pathological conditions\u2014such as cancer cachexia, sepsis, muscular dystrophy, denervation, disuse atrophy, and chronic inflammatory diseases\u2014persistently elevated systemic or local IL-6 levels become a key mediator driving skeletal muscle atrophy, metabolic disorders, and functional decline. This review systematically elaborates on the dual role of IL-6 in skeletal muscle. It provides an in-depth analysis of its downstream signaling pathways (e.g., JAK\/STAT, gp130, MAPK, PI3K-Akt) and upstream regulatory mechanisms (e.g., the Piezo1\/KLF15 axis, calcium signaling, mitochondrial function, oxidative stress). A particular focus is placed on discussing the distinct biological effects of classical IL-6 signaling versus trans-signaling. Furthermore, we address current challenges in research and practice, including the cell specificity of IL-6 signaling, the complexity of its temporal regulation, the definition of physiological versus pathological concentrations, discrepancies between animal models and human diseases, and the plasticity of its function across different pathological contexts. Finally, this review explores the potential of targeting the IL-6 signaling pathway as a therapeutic strategy for skeletal muscle atrophy and related metabolic diseases. Potential interventions include IL-6\/IL-6R monoclonal antibodies, JAK\/STAT inhibitors, gp130 modulators, exercise interventions, and nutritional strategies. This aims to provide a theoretical foundation and novel perspectives for future translational research and clinical interventions.<\/jats:p>","DOI":"10.3390\/ph19060868","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["The Dual Role of Interleukin-6 in the Pathophysiology of Skeletal Muscle: Mechanisms, Challenges, and Therapeutic Prospects"],"prefix":"10.3390","volume":"19","author":[{"given":"Yingyu","family":"Wang","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Nantong University, Nantong 226001, China"},{"name":"Biological Physics Laboratory, Department of Physics and Astronomy, School of Natural Science, The University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jitai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4970-2773","authenticated-orcid":false,"given":"Jiacheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahuan","family":"Gong","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7256-7316","authenticated-orcid":false,"given":"Xinlei","family":"Yao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1889-1561","authenticated-orcid":false,"given":"Hualin","family":"Sun","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration, Key Laboratory of Neuroregeneration of Ministry of Education, Co-Innovation Center of Neuroregeneration, Medical School of Nantong University, Nantong University, Nantong 226001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"ref_1","first-page":"502","article-title":"Monocyte-derived human B-cell growth factor identified as interferon-beta 2 (BSF-2, IL-6)","volume":"239","author":"Tosato","year":"1988","journal-title":"Science"},{"key":"ref_2","first-page":"18","article-title":"Exercise and cytokines with particular focus on muscle-derived IL-6","volume":"7","author":"Pedersen","year":"2001","journal-title":"Exerc. 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