Targeting PIEZO1 ‐ TMEM16F Coupling to Mitigate Sickle Cell Disease Complications

ABSTRACT 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 2+ ‐activated lipid scramblase, as a key mediator of PS exposure downstream of Ca 2+ influx through the mechanosensitive channel PIEZO1 in sickle RBCs. Electrophysiology, imaging, and flow cytometry reveal that deoxygenation‐induced sickling activates PIEZO1, triggering Ca 2+ entry, TMEM16F activation, and PS exposure. This cascade promotes PS + microparticle release, thrombin generation, and RBC adhesion to endothelial cells. Notably, partial PIEZO1 inhibition with benzbromarone, an anti‐gout 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‐occlusion associated with SCD.