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 Ca²⁺-activated lipid scramblase, as a key mediator of PS exposure downstream of Ca²⁺ influx through the mechanosensitive channel PIEZO1 in sickle RBCs. Electrophysiology, imaging, and flow cytometry reveal that deoxygenation-induced sickling activates PIEZO1, triggering Ca²⁺ entry, TMEM16F activation, and PS exposure. This cascade promotes PS⁺ micropart

SUBMITTER: Liang P 

PROVIDER: S-EPMC12637729 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature