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Here, we provide a concise overview of the involvement of IP6 in the ubiquitin-proteasome system (UPS). As an allosteric regulator, a molecular glue, and a potential prosthetic group, IP6 directly impacts the activities of multiple major UPS components. We specifically highlight the structural mechanisms through which IP6 binds to individual proteins or multi-protein complexes to control their functions. The serendipitous discovery of IP6 in various protein structures raises questions about the prevalence, identity, and regulation of soluble inositol polyphosphates in the UPS, which have potential translational implications.<\/jats:p>","DOI":"10.1042\/ebc20253032","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T09:38:26Z","timestamp":1771321106000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Versatile roles of inositol hexakisphosphate in the ubiquitin-proteasome system"],"prefix":"10.1042","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8828-7701","authenticated-orcid":false,"given":"Domnita-Valeria","family":"Rusnac","sequence":"first","affiliation":[{"name":"1Department of Pharmacology, University of Washington, Seattle, WA, 98195, U.S.A."},{"name":"2Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1039-1581","authenticated-orcid":false,"given":"Ning","family":"Zheng","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology, University of Washington, Seattle, WA, 98195, U.S.A."},{"name":"2Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9884-1865","authenticated-orcid":false,"given":"Xiaowen","family":"Xie","sequence":"additional","affiliation":[{"name":"1Department of Pharmacology, University of Washington, Seattle, WA, 98195, U.S.A."},{"name":"3School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"2026021704382412300_EBC-2025-3032C1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/306067a0","article-title":"Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate","volume":"306","author":"Streb","year":"1983","journal-title":"Nature"},{"key":"2026021704382412300_EBC-2025-3032C2","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1152\/physrev.00006.2016","article-title":"The inositol trisphosphate\/calcium signaling pathway in health and disease","volume":"96","author":"Berridge","year":"2016","journal-title":"Physiol. 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