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Here, we demonstrate that overexpressed MDM2 functions as an important pathogenic driver in these malignancies, rewiring oncogenic programs through both p53\u2010independent chromatin occupancy to regulate active transcription and conventional proteasome\u2010mediated p53 degradation leading to pathway suppression. To leverage this dependency for targeted eradication of pediatric sarcomas with MDM2 overexpression, we develop MDM2\u2010recruiting proteolysis\u2010targeting chimeras that selectively degrade the CDK9\/Cyclin T complex (P\u2010TEFb). Among the lead compounds, dCDK9\u2010010 demonstrates superior activity compared to its parental CDK9 inhibitor or MDM2 antagonist either alone or in combination, by coordinatedly disrupting the MDM2\u2010p53 axis and super\u2010enhancer\u2010driven transcription. Remarkably, the transcriptional effects of P\u2010TEFb degradation by dCDK9\u2010010 are phenocopied by MDM2\u2010mediated BET degradation, resulting in potent anti\u2010sarcoma efficacy alongside a favorable therapeutic index and minimal toxicity in nonmalignant cells. Moreover, these MDM2\u2010recruiting transcriptional\/epigenetic machinery degraders (termed MDM2\u2010TEMADs) consistently impair the homologous recombination repair pathway and confer synthetic lethality with PARP inhibitors. Together, this work elucidates MDM2's central role in pediatric sarcoma pathogenesis and presents dCDK9\u2010010 as a first\u2010in\u2010class, MDM2\u2010recruiting P\u2010TEFb degrader and an exemplary MDM2\u2010TEMAD that enables precise targeting of MDM2\u2010dependent oncogenic transcriptional addiction.<\/jats:p>","DOI":"10.1002\/advs.202523088","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:09:34Z","timestamp":1781860174000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Harnessing MDM2\u2010Mediated Targeted Degradation of Transcriptional and Epigenetic Machinery to Disrupt Oncogenic Addictions in Pediatric Sarcoma"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3322-0418","authenticated-orcid":false,"given":"Jiawei","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Surgical Oncology Children's Hospital 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