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In\u2010vitro studies demonstrated TST's dose\u2010\/time\u2010dependent suppression of RMS proliferation (IC50 4.986\u20139.764\u00a0\u03bcmol\/L), migration and invasion, G0\/G1 cell cycle arrest, and apoptosis induction. In vivo, TST (3.4\u00a0mg\/mL, 4\u00a0weeks) significantly inhibited tumor growth (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05 vs. phosphate buffered saline [PBS]) without organ toxicity. RNA sequencing identified the phosphatidylinositol 3\u2010kinase\/protein kinase B (PI3K\u2010AKT) pathway as the primary suppressed pathway (False Discovery Rate [FDR]\u00a0&lt;\u00a00.05), with concurrent downregulation of downstream regulators (<jats:italic>AKT, JAK, CDKs<\/jats:italic>). This was confirmed by PI3K activator 740 Y\u2010P rescue experiments, which partially reversed the effects of TST (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05). These findings establish TST as a multi\u2010mechanism PI3K\u2010AKT inhibitor for refractory RMS while validating Connectivity Map (Cmap)\u2010driven drug repurposing for pediatric oncology.<\/jats:p>","DOI":"10.1002\/pdi3.70014","type":"journal-article","created":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T12:15:10Z","timestamp":1752408910000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thiostrepton Suppresses the Progression of Rhabdomyosarcoma by Inhibiting the PI3K\u2010AKT Signaling Pathway"],"prefix":"10.1002","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0931-5810","authenticated-orcid":false,"given":"Yu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Urology Children's Hospital of Chongqing Medical University National Clinical Research Center for Child Health and Disorders Ministry of Education Key Laboratory of Child Development and Disorders 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