{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T15:03:33Z","timestamp":1779721413361,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,21]]},"group-title":"Pharmacology and Toxicology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Both rare and common variants in the SRY-Box Transcription Factor 17 (\n                    <jats:italic>SOX17<\/jats:italic>\n                    ) locus are associated with pulmonary arterial hypertension (PAH). SOX17 dysregulation leads to pulmonary artery endothelial cell (PAEC) dysfunction and the obstructive remodelling that characterises PAH.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Hypothesis<\/jats:title>\n                  <jats:p>\n                    Impaired\n                    <jats:italic>SOX17<\/jats:italic>\n                    expression contributes to the pathogenesis of PAH. Restoring the function of SOX17 or its downstream targets using compounds that mimic its transcriptomic signature will rescue PAEC dysfunction and prevent PAH development.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods and Results<\/jats:title>\n                  <jats:p>\n                    We defined thousands of genes with direct SOX17 genomic binding sites and identified important potential binding partners, including ETS-transcription factors such as ERG by ChIP-seq in PAECs. Through the integration of three PAEC RNA-seq datasets involving overexpression and silencing of\n                    <jats:italic>SOX17<\/jats:italic>\n                    , we defined a robust SOX17 transcriptomic signature. In PAH patients, circulating plasma protein levels of 10 SOX17 signature genes were associated with the\n                    <jats:italic>SOX17<\/jats:italic>\n                    common risk variants. This included\n                    <jats:italic>EFNB2<\/jats:italic>\n                    and\n                    <jats:italic>UNC5B<\/jats:italic>\n                    ; knockdown of these genes altered the viability and apoptosis of PAECs in response to TNF\u03b1 treatment. The drug-transcriptome database Connectivity Map (CMap) was used to predict novel potential therapeutic compounds to correct the SOX17 transcriptomic signature. Five compounds were selected for\n                    <jats:italic>in vitro<\/jats:italic>\n                    testing and were able to partially reinstate SOX17 target gene expression in PAECs. One compound, BX-912, was selected for\n                    <jats:italic>in vivo<\/jats:italic>\n                    testing as it corrected the levels of multiple target genes, including suppressing Runt-related transcription factor-1 (\n                    <jats:italic>RUNX1<\/jats:italic>\n                    ). BX-912 blocked the development of pulmonary hypertension in mice lacking the\n                    <jats:italic>SOX17<\/jats:italic>\n                    enhancer associated with human disease.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    We have demonstrated the therapeutic potential of targeting SOX17 in PAH through correction of its gene targets, identifying BX-912 as a lead compound with\n                    <jats:italic>in vivo<\/jats:italic>\n                    efficacy.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.14.725284","type":"posted-content","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T15:25:39Z","timestamp":1779377139000},"source":"Crossref","is-referenced-by-count":0,"title":["Identification of drug candidates for rescue of SOX17 gene targets in pulmonary arterial hypertension"],"prefix":"10.64898","author":[{"given":"Eleni","family":"Vasilaki","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, UK"},{"name":"Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bedia","family":"Akosman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Song","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Hammersmith Hospital, Imperial College, London, UK"},{"name":"Guangzhou Medical University, 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