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Immunol."],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) is frequently associated with sarcopenia, a debilitating condition of muscle wasting driven by complex tumor\u2013muscle cross-talk. To unravel the regulatory mechanisms underlying this phenotype, we reconstructed a comprehensive signaling network integrating inflammatory, anabolic, catabolic, and proteolytic pathways. The network was translated into a mechanistic mathematical model using ordinary differential equations, enabling dynamic simulations of pathway activity. Flux analysis revealed that only a limited number of reactions dominate system behavior, with cytoplasmic IL-6 export and SMAD2\/3\u20134 mediated induction of MuRF1 and Atrogin-1 emerging as major control points for muscle protein breakdown. Crosstalk analysis identified these proteolytic regulators as central hubs, integrating signals from inflammatory cytokines, oxidative stress, and transcriptional modulators. Principal component analysis further confirmed that sarcopenic progression is governed by a compact regulatory core, with IL-6\/STAT3, myostatin\/SMAD, and FOXO\/NF-\u03baB pathways converging on MuRF1 and Atrogin-1. Experimental validation using immunofluorescence-based confocal microscopy demonstrated increased expression and altered localization of these ubiquitin ligases in C2C12 cells co-cultured with lung cancer lines, corroborating model predictions. Together, these findings provide a systems-level framework that transforms broad observations of inflammation into ranked therapeutic targets and support combined strategies aimed at blocking the IL-6\/STAT3\u2013myostatin\/SMAD\u2013FOXO1\/3\u2013MuRF1\/Atrogin-1 axis to mitigate NSCLC-associated sarcopenia.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1885023","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T05:29:46Z","timestamp":1785734986000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["IL-6 signaling orchestrates proteolytic hubs MuRF1 and Atrogin-1 in NSCLC induced sarcopenia"],"prefix":"10.3389","volume":"17","author":[{"given":"Gautam","family":"Kumar","sequence":"first","affiliation":[{"name":"Systems Medicine Laboratory, BRIC- National Centre for Cell Science, NCCS Complex, Ganeshkhind","place":["Pune, India"]},{"name":"Regional Centre for Biotechnology","place":["Faridabad, Haryana, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailza","family":"Singh","sequence":"additional","affiliation":[{"name":"Systems Medicine Laboratory, BRIC- National Centre for Cell Science, NCCS Complex, Ganeshkhind","place":["Pune, India"]},{"name":"Regional Centre for Biotechnology","place":["Faridabad, Haryana, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature25183","article-title":"The biology and management of non-small cell lung cancer","volume":"553","author":"Herbst","year":"2018","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.21037\/jtd.2018.08.34","article-title":"Sarcopenia in resected non-small cell lung cancer: let\u2019s move to patient-directed strategies","volume":"10","author":"Icard","year":"2018","journal-title":"J Thorac Dis"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2447","DOI":"10.1038\/s41598-019-39120-6","article-title":"Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study","volume":"9","author":"Shiroyama","year":"2019","journal-title":"Sci Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/jso.24025","article-title":"The impact of sarcopenia on survival and complications in surgical oncology: A review of the current literature","volume":"112","author":"Joglekar","year":"2015","journal-title":"J Surg Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000003164","article-title":"Sarcopenia is an independent predictor of severe postoperative complications and long-term survival after radical gastrectomy for gastric cancer: Analysis from a large-scale cohort","volume":"95","author":"Zhuang","year":"2016","journal-title":"Med (Baltimore)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2005.03.014","article-title":"The pivotal role of cytokines in muscle wasting during cancer","volume":"37","author":"Argil\u00e9s","year":"2005","journal-title":"Int J Biochem Cell Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.jamda.2019.12.012","article-title":"Asian Working Group for Sarcopenia: 2019 consensus update on sarcopenia diagnosis and treatment","volume":"21","author":"Chen","year":"2020","journal-title":"J Am Med Dir Assoc"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.11138\/ccmbm\/2014.11.3.177","article-title":"Clinical definition of sarcopenia","volume":"11","author":"Santilli","year":"2014","journal-title":"Clin cases Miner Bone Metab Off J Ital Soc Osteoporosis Miner Metab Skelet Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262412147","article-title":"Sarcopenia in the aging process: Pathophysiological mechanisms, clinical implications, and emerging therapeutic approaches","volume":"26","author":"Ara\u00fajo","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2017.0315","article-title":"Acute sarcopenia secondary to hospitalisation - 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