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Herein, we designed structurally optimized HyT\u2010based degraders by covalently conjugating hydrophobic amino acid tags to ER\u03b1\u2010targeting ligands via alkane linkers of varying lengths, identifying the lead compound\n                    <jats:bold>VI\u201010h<\/jats:bold>\n                    .\n                    <jats:bold>VI\u201010h<\/jats:bold>\n                    exhibited potent antiproliferative activity and efficient ER\u03b1 degradation in endocrine\u2010resistant breast cancer cells (LCC2, MCF\u20107\n                    <jats:sup>D538G<\/jats:sup>\n                    , MCF\u20107\n                    <jats:sup>Y537S<\/jats:sup>\n                    , and MCF\u20107\n                    <jats:sup>EGFR<\/jats:sup>\n                    ) and superior antitumor activity compared to the clinical drug fulvestrant (\n                    <jats:bold>Ful<\/jats:bold>\n                    ) in MCF\u20107 and tamoxifen\u2010resistant LCC2 xenograft models. To elucidate the HyT\u2010mediated degradation mechanism, we synthesized biotin\u2010conjugated HyTs (\n                    <jats:bold>biotin\u2010Lys<\/jats:bold>\n                    and\n                    <jats:bold>biotin\u2010Trp<\/jats:bold>\n                    ) and performed pull\u2010down assays combined with mass spectrometry. Our results unveiled that\n                    <jats:bold>VI\u201010h<\/jats:bold>\n                    selectively recruits heat shock protein 27 (HSP27) as a non\u2010canonical E3 ligase adaptor protein, forms an ER\u03b1\u2013HSP27\u2013RING1 ternary complex to promote ER\u03b1 degradation, disrupts estrogen\u2010dependent oncogenic networks, and circumvents the drug resistance associated with conventional CRBN\u2010 or VHL\u2010dependent E3 ligase\u2010recruiting degraders. This study clarifies a HyT\u2010mediated ER\u03b1 degradation mechanism and supports the feasibility of using HyT degraders to overcome resistance to conventional E3 ligase\u2010recruiting strategies and endocrine\u2010resistant breast cancer, thereby establishing a molecular design strategy for next\u2010generation targeted degraders.\n                  <\/jats:p>","DOI":"10.1002\/anie.202525741","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T16:26:56Z","timestamp":1779812816000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydrophobic Tag Degraders Overcome Endocrine\u2010Resistant Breast Cancer by Recruiting HSP27\u2010Mediated E3 Ligase Complex for ER\u03b1 Proteasomal Degradation"],"prefix":"10.1002","volume":"65","author":[{"given":"Lilan","family":"Xin","sequence":"first","affiliation":[{"name":"Department of Hematology School of Pharmaceutical Sciences Zhongnan Hospital of Wuhan University, Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zemin","family":"Song","sequence":"additional","affiliation":[{"name":"Taikang Center for Life and Medical Sciences School of Basic Medical Sciences Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Cui","sequence":"additional","affiliation":[{"name":"School of Sports Medicine Wuhan Sports University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology School of Pharmaceutical Sciences Zhongnan Hospital of Wuhan University, Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hematology School of Pharmaceutical Sciences Zhongnan Hospital of Wuhan University, 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