{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:59:34Z","timestamp":1785437974320,"version":"3.56.0"},"posted":{"date-parts":[[2025,11,12]]},"group-title":"Cancer Biology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["CA294365"],"award-info":[{"award-number":["CA294365"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AR081487"],"award-info":[{"award-number":["AR081487"]}],"id":[{"id":"https:\/\/ror.org\/006zn3t30","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma arising from mesenchymal progenitors with skeletal muscle features. The unfolded protein response (UPR) maintains proteostasis during endoplasmic reticulum stress, with the IRE1\u03b1-XBP1 axis representing a key signaling branch. Here, we demonstrate that components of this pathway are significantly upregulated in RMS cell lines and primary tumors. Genetic or pharmacological inhibition of IRE1\u03b1 or spliced XBP1 (sXBP1) suppresses cell proliferation, promotes terminal myogenic differentiation, and enhances vincristine-induced cytotoxicity in RMS cells. Silencing of sXBP1 further reduces the cancer stem-like cell population and impairs migration and invasion. Mechanistically, IRE1\u03b1-XBP1 signaling promotes RMS progression through sXBP1-dependent upregulation of BMPR1A and subsequent activation of BMP-SMAD1 signaling. Consistently, inducible knockdown of sXBP1 or pharmacological inhibition of IRE1\u03b1 endonuclease activity significantly attenuates xenograft RMS growth. Collectively, these findings identify the IRE1\u03b1-XBP1 axis as a critical regulator of RMS growth, differentiation, and chemoresistance, and support its therapeutic targeting in RMS.<\/jats:p>","DOI":"10.1101\/2025.11.10.687677","type":"posted-content","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T18:30:17Z","timestamp":1762972217000},"source":"Crossref","is-referenced-by-count":1,"title":["Targeting the IRE1\u03b1-XBP1 signaling axis impairs tumor growth and promotes myogenic differentiation in rhabdomyosarcoma"],"prefix":"10.64898","author":[{"given":"Anh Tuan","family":"Vuong","sequence":"first","affiliation":[{"name":"Institute of Muscle Biology and Cachexia, University of Houston College of Pharmacy, Houston, Texas, USA"},{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniket 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