Liang Pengfei, Wan Yui-Chun Serena, Shan Ke Zoe, Chou Ryan, Zhang Yang, Delahunty Martha, Khandelwal Sanjay, Francis Samuel J, Arepally Gowthami M, Telen Marilyn J, Yang Huanghe
Department of Biochemistry, Duke University School of Medicine, NC 27710, USA.
Department of Medicine, Duke University School of Medicine, NC 27710, USA.
bioRxiv. 2025 May 31:2025.05.27.656389. doi: 10.1101/2025.05.27.656389.
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-activated lipid scramblase, as a key mediator of PS exposure downstream of Ca influx through the mechanosensitive channel PIEZO1 in sickle RBCs. Electrophysiology, imaging and flow cytometry reveal that deoxygenation-induced sickling promotes PIEZO1 activation, triggering Ca entry, TMEM16F activation, and PS exposure. This cascade enhances PS 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.
深入了解镰状细胞病（SCD）的病理生理学对于确定新的治疗靶点至关重要。SCD的一个标志是镰状红细胞（RBC）上异常暴露磷脂酰丝氨酸（PS），这会导致贫血、血栓形成和血管闭塞性危机（VOC）。然而，这种过度PS暴露的潜在机制仍不清楚。在这里，我们确定跨膜蛋白16F（TMEM16F），一种钙激活的脂质翻转酶，是镰状红细胞中通过机械敏感通道PIEZO1的钙内流下游PS暴露的关键介质。电生理学、成像和流式细胞术显示，脱氧诱导的镰变促进PIEZO1激活，触发钙内流、TMEM16F激活和PS暴露。这一级联反应增强了PS微粒释放、凝血酶生成以及RBC与内皮细胞的粘附。值得注意的是，用抗痛风药物苯溴马隆部分抑制PIEZO能抑制这些变化。因此，我们的研究结果定义了镰状红细胞中一种以前未被认识的机械转导途径，并提出了一种独特的治疗策略，以减轻与SCD相关的高凝性和血管闭塞。
