{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T22:26:02Z","timestamp":1783376762015,"version":"3.54.6"},"reference-count":91,"publisher":"American Society for Clinical Investigation","issue":"9","license":[{"start":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T00:00:00Z","timestamp":1683504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,8]]},"abstract":"<jats:p>\n                    Synovial fibroblasts (SFs) are key pathogenic drivers in rheumatoid arthritis (RA). Their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models, and TNF blockade proved efficacious for a high percentage of patients with RA albeit coinducing rare but serious side effects. Aiming to find new potent therapeutics, we applied the L1000CDS\n                    <jats:sup>2<\/jats:sup>\n                    search engine, to repurpose drugs that could reverse the pathogenic expression signature of arthritogenic human TNF\u2013transgenic (\n                    <jats:italic>hTNFtg<\/jats:italic>\n                    ) SFs. We identified a neuroleptic drug, namely amisulpride, which reduced SFs\u2019 inflammatory potential while decreasing the clinical score of\n                    <jats:italic>hTNFtg<\/jats:italic>\n                    polyarthritis. Notably, we found that amisulpride function was neither through its known targets dopamine receptors D2 and D3 and serotonin receptor 7 nor through TNF\u2013TNF receptor I binding inhibition. Through a click chemistry approach, potentially novel targets of amisulpride were identified, which were further validated to repress\n                    <jats:italic>hTNFtg<\/jats:italic>\n                    SFs\u2019 inflammatory potential ex vivo (\n                    <jats:italic>Ascc3<\/jats:italic>\n                    and\n                    <jats:italic>Sec62<\/jats:italic>\n                    ), while phosphoproteomics analysis revealed that treatment altered important fibroblast activation pathways, such as adhesion. Thus, amisulpride could prove beneficial to patients experiencing RA and the often-accompanying comorbid dysthymia, reducing SF pathogenicity along with its antidepressive activity, serving further as a \u201clead\u201d compound for the development of novel therapeutics against fibroblast activation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.165024","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T12:01:47Z","timestamp":1680609707000},"source":"Crossref","is-referenced-by-count":12,"title":["Repurposing the antipsychotic drug amisulpride for targeting synovial fibroblast activation in arthritis"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5824-1876","authenticated-orcid":true,"given":"Dimitra","family":"Papadopoulou","sequence":"first","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Centre Alexander Fleming\u201d, Vari, 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