{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T04:23:40Z","timestamp":1792211020102,"version":"4.4.0"},"reference-count":72,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001422","name":"American Society of Hematology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001422","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM153196"],"award-info":[{"award-number":["R35GM153196"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    A deeper understanding of sickle cell disease (SCD) pathophysiology is critical for identifying novel therapeutic targets. A hallmark of SCD is abnormal phosphatidylserine (PS) exposure on sickle red blood cells (RBCs), which contributes to anemia, thrombosis, and vaso\u2010occlusive crises (VOC). However, the mechanisms underlying this excessive PS exposure remain unclear. Here, we identify TMEM16F, a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010activated lipid scramblase, as a key mediator of PS exposure downstream of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx through the mechanosensitive channel PIEZO1 in sickle RBCs. Electrophysiology, imaging, and flow cytometry reveal that deoxygenation\u2010induced sickling activates PIEZO1, triggering Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry, TMEM16F activation, and PS exposure. This cascade promotes PS\n                    <jats:sup>+<\/jats:sup>\n                    microparticle release, thrombin generation, and RBC adhesion to endothelial cells. Notably, partial PIEZO1 inhibition with benzbromarone, an anti\u2010gout drug, suppresses these effects. Our findings define a previously unrecognized mechanotransduction pathway in sickle RBCs and propose a unique therapeutic strategy to mitigate hypercoagulability and vaso\u2010occlusion associated with SCD.\n                  <\/jats:p>","DOI":"10.1002\/ajh.70086","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T21:11:53Z","timestamp":1759957913000},"page":"2261-2275","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Targeting\n                    <scp>PIEZO1<\/scp>\n                    \u2010\n                    <scp>TMEM16F<\/scp>\n                    Coupling to Mitigate Sickle Cell Disease Complications"],"prefix":"10.1002","volume":"100","author":[{"given":"Pengfei","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Biochemistry Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui\u2010Chun S.","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke Z.","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Delahunty","sequence":"additional","affiliation":[{"name":"Department of Medicine Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5661-3856","authenticated-orcid":false,"given":"Sanjay","family":"Khandelwal","sequence":"additional","affiliation":[{"name":"Department of Medicine Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Francis","sequence":"additional","affiliation":[{"name":"Department of Surgery Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gowthami M.","family":"Arepally","sequence":"additional","affiliation":[{"name":"Department of Medicine Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn J.","family":"Telen","sequence":"additional","affiliation":[{"name":"Department of Medicine Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9521-9328","authenticated-orcid":false,"given":"Huanghe","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Duke University School of Medicine  Durham North Carolina USA"},{"name":"Department of Medicine Duke University School of Medicine  Durham North Carolina USA"},{"name":"Department of Neurobiology Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amepre.2009.12.022"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmacy10050123"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(23)00096-0"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020001469"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.5.1873.1873"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-11-3416"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V58.2.398.398"},{"key":"e_1_2_11_9_1","article-title":"Of Macrophages and Red Blood Cells; a Complex Love Story","volume":"5","author":"Back D. 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O.Romero M.Bade L.Elsherif et\u00a0al. \u201cEnhanced PIEZO1 Function Contributes to the Pathogenesis of Sickle Cell Disease \u201d preprint bioRxiv 2025.03.19.643952 2025.","DOI":"10.1101\/2025.03.19.643952"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2024.11.3120"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1214596109"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000122"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.122.000638"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/7058016"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1101\/2020.10.28.20221358"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09778-7"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba0310"}],"container-title":["American Journal of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajh.70086","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T09:21:32Z","timestamp":1762852892000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajh.70086"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":72,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/ajh.70086"],"URL":"https:\/\/doi.org\/10.1002\/ajh.70086","archive":["Portico"],"relation":{},"ISSN":["0361-8609","1096-8652"],"issn-type":[{"value":"0361-8609","type":"print"},{"value":"1096-8652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,8]]},"assertion":[{"value":"2025-06-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}