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Glutathione peroxidase 4 (GPX4) is a key target for inducing ferroptosis, but achieving sustained and potent inhibition remains challenging with conventional enzymatic inhibitors. Herein, we report the first small\u2010molecule GPX4 degraders that incorporate either electrophilic warheads or a minimal azide group as an E3 recruitment ligand. The azide\u2010based degrader\n                    <jats:bold>DK\u20105070<\/jats:bold>\n                    effectively drives potent GPX4 degradation, achieving a DC\n                    <jats:sub>50<\/jats:sub>\n                    of 17.4 nM and a Dmax of 84%, thereby outperforming larger PROTAC\u2010based degraders. Notably,\n                    <jats:bold>DK\u20115070<\/jats:bold>\n                    exhibits potent antitumor activity both in vitro (IC\n                    <jats:sub>50<\/jats:sub>\n                    = 47.21 nM) and in vivo (TGI = 41.8%), demonstrating significant efficacy as a GPX4 degrader. Mechanistic studies reveal that degradation is mediated through recruitment of the oncogenic E3 ligase UHRF1, which is frequently overexpressed in tumors, underscoring the potential for tumor\u2010specific protein degradation. This demonstrated small\u2010molecule degraders that recruit UHRF1 to facilitate targeted degradation of GPX4. In this system, the azide group functions as a minimal recruitment ligand, thereby expanding the E3 ligase toolbox and offering a promising strategy for targeted cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.77201","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T13:51:46Z","timestamp":1787147506000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A New Recruitable E3 Ligase UHRF1 Supporting Targeted Protein Degradation: A Minimal Azide as a Recruitment Ligand"],"prefix":"10.1002","author":[{"given":"Zehong","family":"Lin","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University  Guangzhou China"},{"name":"Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou 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Assessment Jinan University  Guangzhou China"},{"name":"Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinzhe","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University  Guangzhou China"},{"name":"Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University  Guangzhou China"},{"name":"Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou 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 Guangzhou China"},{"name":"Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University  Guangzhou China"},{"name":"Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9016-812X","authenticated-orcid":false,"given":"Ke","family":"Ding","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University  Guangzhou China"},{"name":"Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University  Guangzhou China"},{"name":"Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0859-3923","authenticated-orcid":false,"given":"Tongzheng","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Jinan University  Guangzhou China"},{"name":"Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs Jinan University  Guangzhou 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