{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:48:32Z","timestamp":1782280112035,"version":"3.54.5"},"posted":{"date-parts":[[2025,5,31]]},"group-title":"Physiology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH","award":["R35GM153196"],"award-info":[{"award-number":["R35GM153196"]}]},{"DOI":"10.13039\/100001422","name":"American Society of Hematology","doi-asserted-by":"crossref","award":["ASH Scholar Award"],"award-info":[{"award-number":["ASH Scholar Award"]}],"id":[{"id":"10.13039\/100001422","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001422","name":"American Society of Hematology","doi-asserted-by":"crossref","award":["ASH Graduate Hematology Award"],"award-info":[{"award-number":["ASH Graduate Hematology Award"]}],"id":[{"id":"10.13039\/100001422","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,31]]},"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-occlusive 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                  -activated 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-induced sickling promotes PIEZO1 activation, triggering Ca\n                  <jats:sup>2+<\/jats:sup>\n                  entry, TMEM16F activation, and PS exposure. This cascade enhances 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-gout drug, suppresses these changes. Our findings thus define a previously unrecognized mechanotransduction pathway in sickle RBCs and propose a unique therapeutic strategy to mitigate hypercoagulability and vaso-occlusion associated with SCD.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Brief Summary<\/jats:title>\n                  <jats:p>Enhanced PIEZO1 activation in sickle red blood cells promotes TMEM16F scramblase-mediated phosphatidylserine exposure and subsequent sickle cell disease complications. Disrupting this coupling presents a potential therapeutic strategy.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.27.656389","type":"posted-content","created":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T02:35:13Z","timestamp":1748745313000},"source":"Crossref","is-referenced-by-count":3,"title":["Targeting PIEZO1-TMEM16F Coupling to Mitigate Sickle Cell Disease Complications"],"prefix":"10.64898","author":[{"given":"Pengfei","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui-Chun Serena","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke Zoe","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Delahunty","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Khandelwal","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel J.","family":"Francis","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gowthami M.","family":"Arepally","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn J.","family":"Telen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, NC 27710, 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, NC 27710, USA"},{"name":"Department of Medicine, Duke University School of Medicine, NC 27710, USA"},{"name":"Department of Neurobiology, Duke University School of Medicine, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041200171442000_2025.05.27.656389v1.1","first-page":"987","article-title":"Relationship between morphologic characteristics of sickle cells and method of deoxygenation","volume":"104","year":"1984","journal-title":"J Lab Clin Med"},{"key":"2026041200171442000_2025.05.27.656389v1.2","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2007.1.91"},{"key":"2026041200171442000_2025.05.27.656389v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2003.07.011"},{"key":"2026041200171442000_2025.05.27.656389v1.4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-08-110098"},{"key":"2026041200171442000_2025.05.27.656389v1.5","doi-asserted-by":"publisher","DOI":"10.1186\/s42358-019-0080-x"},{"key":"2026041200171442000_2025.05.27.656389v1.6","doi-asserted-by":"publisher","DOI":"10.1021\/bi200770q"},{"key":"2026041200171442000_2025.05.27.656389v1.7","doi-asserted-by":"crossref","unstructured":"Barak, M. , C. 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