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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:p>Tumor reliance on antioxidant defenses creates a vulnerability to ferroptosis, yet strategies to therapeutically disable these systems remain limited. Here, we identify targeted degradation of the selenium uptake receptor lipoprotein receptor-related protein 8 (LRP8) as an effective approach to decrease the abundance of the ferroptosis-protective enzyme glutathione peroxidase 4 (GPX4). Using bispecific cytokine receptor\u2013targeting chimeras (KineTACs) that couple LRP8 to cytokine receptor internalization pathways, we selectively direct LRP8 to the lysosome for degradation. LRP8 degradation reduces the abundance of several selenoproteins, including GPX4, lowering the cellular threshold for lipid peroxidation and sensitizing cancer cells to ferroptosis. These findings establish receptor-mediated selenium uptake as a critical, targetable node in ferroptosis resistance and demonstrate that extracellular protein degradation can be leveraged to reprogram intracellular translational dependencies in cancer cells. More broadly, this work provides a framework for exploiting nutrient acquisition pathways to overcome therapy resistance.<\/jats:p>","DOI":"10.1073\/pnas.2616933123","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:13:32Z","timestamp":1790784812000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Targeted extracellular degradation of LRP8 promotes ferroptosis in cancer cells"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3172-1340","authenticated-orcid":false,"given":"Fangzhu","family":"Zhao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7410-9226","authenticated-orcid":false,"given":"Alex","family":"Inague","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an7q238","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular and Cell Biology, University of California Berkeley","place":["Berkeley"]},{"id":[{"id":"https:\/\/ror.org\/01an7q238","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Metabolic Biology and Nutrition, University of California Berkeley","place":["Berkeley"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9153-2525","authenticated-orcid":false,"given":"Trenton M.","family":"Peters-Clarke","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8754-5779","authenticated-orcid":false,"given":"Yifei","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Snehal D.","family":"Ganjave","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Miao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi","family":"Yao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2596-1943","authenticated-orcid":false,"given":"Yan","family":"Wu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmaceutical Chemistry, University of California San Francisco","place":["San Francisco"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7900-5685","authenticated-orcid":false,"given":"Madison K. 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