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However, the mechanisms of cachexia and the potential therapeutic interventions remain poorly studied. We observed a significant positive correlation between SIRT1 expression and muscle fiber cross-sectional area in pancreatic cancer patients. Rescuing Sirt1 expression by exogenous expression or pharmacological agents reverted cancer cell\u2013induced myotube wasting in culture conditions and mouse models. RNA-seq and follow-up analyses showed cancer cell\u2013mediated SIRT1 loss induced NF-\u03baB signaling in cachectic muscles that enhanced the expression of FOXO transcription factors and NADPH oxidase 4 (Nox4), a key regulator of reactive oxygen species production. Additionally, we observed a negative correlation between NOX4 expression and skeletal muscle fiber cross-sectional area in pancreatic cancer patients. Knocking out Nox4 in skeletal muscles or pharmacological blockade of Nox4 activity abrogated tumor-induced cachexia in mice. Thus, we conclude that targeting the Sirt1\u2013Nox4 axis in muscles is an effective therapeutic intervention for mitigating pancreatic cancer\u2013induced cachexia.<\/jats:p>","DOI":"10.1084\/jem.20190745","type":"journal-article","created":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T09:52:32Z","timestamp":1594893152000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":67,"title":["SIRT1\u2013NOX4 signaling axis regulates cancer cachexia"],"prefix":"10.1084","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7479-1149","authenticated-orcid":true,"given":"Aneesha","family":"Dasgupta","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surendra K.","family":"Shukla","sequence":"additional","affiliation":[{"name":"The Eppley Institute for Research in 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