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A major factor limiting the effectiveness of ferroptosis induction is the antioxidant activity of glutathione peroxidase 4 (GPX4). Herein, we reported SLC7A11\u2010targeting proteolysis targeting chimeras (PROTACs) to deplete GPX4 and to augment oxidative stress within cancer cells. A bifunctional PROTAC, namely dSLC7A11, ws designed by conjugating the SLC7A11 inhibitor sulfasalazine to the CRBN ligand pomalidomide via an alkyl linker. The rational designed chimera effectively induced ubiquitin\u2010mediated degradation of SLC7A11. Consequently, this inactivated cystine\/glutamate antiporter (System Xc\n                    <jats:sup>\u2212<\/jats:sup>\n                    ), depleted GPX4, and amplified oxidative stress in cancer cells. Notably, dSLC7A11 exhibited superior antitumor efficacy over sulfasalazine alone, and achieved an effect of suppressing tumor growth by &gt;65% in vivo. This study presented a SLC7A11\u2010targeting PROTAC that disrupts the cellular antioxidant defense system, thus establishing a novel PROTAC\u2010based approach for potent ferroptosis induction in cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202504602","type":"journal-article","created":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T12:37:11Z","timestamp":1767098231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Precision Ferroptosis Amplification via SLC7A11\u2010Directed Proteasomal Degradation for Enhanced Cancer Therapy"],"prefix":"10.1002","volume":"15","author":[{"given":"SiJia","family":"Lin","sequence":"first","affiliation":[{"name":"Affiliated Hospital of Jiangsu University  Zhenjiang 212001 P. R. China"},{"name":"College of Pharmaceutical Sciences Jiangsu University  Zhenjiang Jiangsu 212013 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Jiangsu University  Zhenjiang Jiangsu 212013 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Dong","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Jiangsu University  Zhenjiang Jiangsu 212013 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZiYi","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Jiangsu University  Zhenjiang Jiangsu 212013 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Cao","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences Jiangsu University  Zhenjiang Jiangsu 212013 P. R. 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