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Despite its efficacy, mounting evidence has suggested a higher risk of neuropsychiatric adverse effect (NPAE) associated with DTG use, with a limited understanding of the underlying mechanisms. Our laboratory has previously reported a toxic effect of DTG but not bictegravir (BTG) in disrupting the blood\u2013brain barrier (BBB) integrity. The current study aimed to investigate the underlying mechanism of DTG toxicity. Primary cultures of mouse brain microvascular endothelial cells were treated with DTG and BTG at therapeutically relevant concentrations. RNA sequencing, qPCR, western blot analysis, and cell stress assays (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    flux, H2DCFDA, TMRE, MTT) were applied to assess the results. The gene ontology (GO) analysis revealed an enriched transcriptome signature of endoplasmic reticulum (ER) stress following DTG treatment. We demonstrated that therapeutic concentrations of DTG but not BTG activated the ER stress sensor proteins (PERK, IRE1, p\u2010IRE1) and downstream ER stress markers (eIF2\u03b1, p\u2010eIF2\u03b1,\n                    <jats:italic>Hspa5<\/jats:italic>\n                    ,\n                    <jats:italic>Atf4<\/jats:italic>\n                    ,\n                    <jats:italic>Ddit3<\/jats:italic>\n                    ,\n                    <jats:italic>Ppp1r15a<\/jats:italic>\n                    ,\n                    <jats:italic>Xbp1<\/jats:italic>\n                    ,\n                    <jats:italic>spliced\u2010Xbp1<\/jats:italic>\n                    ). In addition, DTG treatment resulted in a transient Ca\n                    <jats:sup>2+<\/jats:sup>\n                    flux, an aberrant mitochondrial membrane potential, and a significant increase in reactive oxygen species in treated cells. Furthermore, we found that prior treatment with ER sensor or ER stress inhibitors significantly mitigated the DTG\u2010induced downregulation of tight junction proteins (Zo\u20101, Ocln, Cldn5) and elevation of pro\u2010inflammatory cytokines and chemokines (\n                    <jats:italic>Il6<\/jats:italic>\n                    ,\n                    <jats:italic>Il23a<\/jats:italic>\n                    ,\n                    <jats:italic>Il12b<\/jats:italic>\n                    ,\n                    <jats:italic>Cxcl1<\/jats:italic>\n                    ,\n                    <jats:italic>Cxcl2<\/jats:italic>\n                    ). The current study provides valuable insights into DTG\u2010mediated cellular toxicity mechanisms, which may serve as a potential explanation for DTG\u2010associated NPAEs in the clinic.\n                  <\/jats:p>","DOI":"10.1096\/fj.202402677rr","type":"journal-article","created":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T04:25:22Z","timestamp":1740198322000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dolutegravir induces endoplasmic reticulum stress at the blood\u2013brain barrier"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6622-8959","authenticated-orcid":false,"given":"Chang","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4938-5745","authenticated-orcid":false,"given":"Qing Rui","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4802-0257","authenticated-orcid":false,"given":"Md. 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