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Adv."],"published-print":{"date-parts":[[2026,7,3]]},"abstract":"<jats:p>\n                    The platelet-surface Ero1\u03b1\u2013protein disulfide isomerase (PDI) system is essential for integrin \u03b1IIb\u03b23 activation and platelet aggregation. Targeting the functional interplay between Ero1\u03b1 and PDI emerges as a promising antithrombotic strategy. Using a tiered high-throughput screen, we identified two clinical-stage compounds, Luminespib and AZ5104, as selective inhibitors of the Ero1\u03b1-PDI interaction. They bind a hydrophobic pocket in the PDI\n                    <jats:italic toggle=\"yes\">b<\/jats:italic>\n                    \u02b9 domain, inhibiting the pathway in biochemical and cellular assays without affecting other PDI family members. The antiplatelet effects of Luminespib and AZ5104 were abolished in megakaryocyte-specific\n                    <jats:italic toggle=\"yes\">Pdi<\/jats:italic>\n                    or\n                    <jats:italic toggle=\"yes\">Ero1a<\/jats:italic>\n                    knockout mice, confirming on-target specificity. Mechanistically, they concurrently inhibit Ero1\u03b1-PDI\u2013driven extracellular integrin activation and intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling. Both compounds potently reduced arterial thrombosis in mice without prolonging bleeding time. Our work establishes Luminespib and AZ5104 as clinical-stage antithrombotic agents that target the platelet Ero1\u03b1-PDI system, offering an effective strategy to achieve potent antithrombosis without compromising hemostasis.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg2095","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T17:58:28Z","timestamp":1783101508000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Luminespib and AZ5104 are effective antithrombotic drugs via targeting the platelet Ero1\u03b1-PDI pathway"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4233-4984","authenticated-orcid":true,"given":"Shuo","family":"Sun","sequence":"first","affiliation":[{"name":"State Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China."},{"name":"College of Life Sciences, 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