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Disrupting ERAD has been proposed as a therapeutic strategy to overcome proteasome inhibitor resistance; however, the identification of novel inhibitors has been limited. To address this, we conducted a cell-based high-throughput screen using the FDA repurposing library and identified omaveloxolone (RTA408) as a potent ERAD inhibitor that selectively impairs the degradation of ER luminal and membrane substrates, without affecting the degradation of key cytosolic proteins that are implicated in disease relapse. Surprisingly, although ER stress response pathways are activated after ERAD inhibition in MM, we find that apoptosis is mediated by altered lipid raft organization, leading to aberrant activation of the death-inducing signaling complex (DISC) and caspase 8 in the extrinsic apoptotic pathway. Notably, ERAD inhibition by RTA408 is cytotoxic to primary malignant plasma cells, including those resistant to proteasome inhibitors, and demonstrates in vivo anti-myeloma activity. Our findings establish a novel ERAD inhibitor, which is a valuable tool to dissect ERAD biology, and provide pre-clinical evidence for RTA408 as a therapeutic agent in MM.<\/jats:p>","DOI":"10.1038\/s41419-026-08526-2","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T12:28:37Z","timestamp":1773059317000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8597-3025","authenticated-orcid":false,"given":"Erin M.","family":"Kropp","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Matono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia Y.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron M.","family":"Robida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0440-4964","authenticated-orcid":false,"given":"Malathi","family":"Kandarpa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jineigh L.","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryndon J.","family":"Oleson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Alt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3361-3981","authenticated-orcid":false,"given":"Moshe","family":"Talpaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Pianko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4982-1024","authenticated-orcid":false,"given":"Qing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"8526_CR1","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.3324\/haematol.2012.064923","volume":"97","author":"LI Aronson","year":"2012","unstructured":"Aronson LI, Davies FE. 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EMK is employed by the Department of Veteran\u2019s Affairs; these contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. MJP receives honoraria\/consulting from Janssen\/Johnson & Johnson, Bristol Myers Squibb, Sanofi, GlaxoSmithKline, Pfizer and Research Funding (To Institution): AbbVie, AstraZeneca, Bristol Myers Squibb, Janssen, Pfizer, Sanofi, and Regeneron.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal studies were approved by the Institutional Animal Care and Use Committees and performed in the Unit for Laboratory Animal Medicine at the University of Michigan. All procedures involving animal care and use were conducted in accordance with ethical and institutional guidelines. Fresh bone marrow or peripheral blood samples were obtained for the University of Michigan hematologic malignancy repository bank after obtaining informed consent under Institutional Review Board-approved studies HUM00002815 and HUM00066564 at the University of Michigan. For this study, de-identified samples were obtained from the hematologic malignancy repository bank and all biospecimen studies were conducted in accordance with ethical and Institutional Review Board guidelines at the University of Michigan.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"303"}}