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The molecular hallmark of VEXAS is somatic mutations at methionine 41 (M41) in the E1 ubiquitin enzyme, UBA1. These mutations induce a protein isoform switch, but the mechanisms underlying disease pathogenesis remain unclear. Here, we developed a human cell model of VEXAS syndrome by engineering the male monocytic THP1 cell line to express the common UBA1<jats:sup>M41V<\/jats:sup> mutation. We found that mutant UBA1<jats:sup>M41V<\/jats:sup> cells exhibit aberrant UBA1 isoform expression, increased vacuolization, and upregulation of the unfolded protein response, recapitulating key features of VEXAS. Moreover, proteomic analyses revealed dysregulated ubiquitination and proteotoxic stress in UBA1<jats:sup>M41V<\/jats:sup> cells, with alterations in inflammatory and stress-response pathways. Functional studies demonstrated that UBA1<jats:sup>M41V<\/jats:sup> cells were highly sensitive to genetic or pharmacological inhibition of E1 ubiquitin enzymes. Treatment with the E1 enzyme inhibitor TAK-243 preferentially suppressed colony formation of UBA1<jats:sup>M41V<\/jats:sup> cells as compared to WT cells. Moreover, UBA1<jats:sup>M41V<\/jats:sup> cells exhibited greater sensitivity to TAK-243 in competition assays and showed increased apoptosis. Interestingly, TAK-243 preferentially inhibited UBA6 activity over UBA1, suggesting that UBA6 may compensate for UBA1 dysfunction in UBA1<jats:sup>M41V<\/jats:sup> cells. Targeting UBA6 using shRNA or the UBA6-specific inhibitor phytic acid further revealed an acquired dependency on UBA6 in UBA1<jats:sup>M41V<\/jats:sup> cells. Phytic acid selectively impaired growth and colony formation in UBA1<jats:sup>M41V<\/jats:sup> cells while sparing WT cells, highlighting a potential therapeutic vulnerability. Together, these findings establish a novel human model of VEXAS syndrome, identify key roles for UBA1 and UBA6 in disease pathogenesis, and demonstrate that UBA6 inhibition represents a promising therapeutic strategy for selectively targeting UBA1 mutant clones.<\/jats:p>","DOI":"10.1038\/s41375-025-02671-x","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T04:01:34Z","timestamp":1751256094000},"page":"1997-2009","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Characterization of E1 enzyme dependencies in mutant-UBA1 human cells reveals UBA6 as a novel therapeutic target in VEXAS syndrome"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7859-7252","authenticated-orcid":false,"given":"Courtnee A.","family":"Clough","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Cunningham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6973-902X","authenticated-orcid":false,"given":"Sophia Y.","family":"Philbrook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Hueneman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7241-8770","authenticated-orcid":false,"given":"Avery M.","family":"Sampson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4671-962X","authenticated-orcid":false,"given":"Kwangmin","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5316-3351","authenticated-orcid":false,"given":"Kenneth D.","family":"Greis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5771-7462","authenticated-orcid":false,"given":"Daniel","family":"Starczynowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"2671_CR1","doi-asserted-by":"crossref","unstructured":"Fhu CW, Ali A. 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