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We aimed to identify the molecular insults of mutations, focusing on collagen folding, to establish if targeting protein folding represents a potential therapeutic approach. Analysis of two novel\n                    <jats:italic>COL3A1<\/jats:italic>\n                    glycine mutations, G189S and G906R, in primary patient fibroblast cultures revealed secretion of misfolded collagen III and intracellular collagen retention leading to lower extracellular collagen levels. This was associated with matrix defects, endoplasmic reticulum (ER) stress, reduced cell proliferation and apoptosis. The ER stress was mediated by activation of IRE1 and PERK signalling arms with evidence of allelic heterogeneity. To establish if promoting ER protein folding capacity or protein degradation represents novel therapeutic avenues, we investigated the efficacy of FDA-approved small molecules. The chemical chaperone 4-phenylbutyric acid (PBA) rescued the ER stress and thermostability of secreted collagen leading to reduced apoptosis and matrix defects, and its efficacy was influenced by duration, dosage and allelic heterogeneity. Targeting protein degradation with carbamazepine (CBZ), or PBA-CBZ in combination did not increase treatment efficacy. These data establish that ER stress is a molecular mechanism in vEDS that can be influenced by the position of\n                    <jats:italic>COL3A1<\/jats:italic>\n                    mutation. It combines with matrix defects due to reduced collagen III levels and\/or mutant protein secretion to vEDS pathogenesis. Targeting protein folding using FDA-approved chemical chaperones represents a putative mechanism-based therapeutic approach for vEDS that can rescue intra- and extracellular defects.\n                  <\/jats:p>","DOI":"10.1038\/s41420-025-02476-y","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T04:54:04Z","timestamp":1745556844000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome"],"prefix":"10.1038","volume":"11","author":[{"given":"Ramla","family":"Omar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0519-9737","authenticated-orcid":false,"given":"Michelle AW","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Gonzalez-Trueba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron R.","family":"Thomson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spyridonas","family":"Lianos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Snoopy","family":"Hazarika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar HMEH","family":"El Abdallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malak A.","family":"Ammar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Cassels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5404-475X","authenticated-orcid":false,"given":"Alison M.","family":"Michie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil J.","family":"Bulleid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fransiska","family":"Malfait","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4282-449X","authenticated-orcid":false,"given":"Tom","family":"Van Agtmael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"2476_CR1","doi-asserted-by":"publisher","first-page":"100090","DOI":"10.1016\/j.mbplus.2021.100090","volume":"12","author":"R Omar","year":"2021","unstructured":"Omar R, Malfait F, Van Agtmael T. 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