Small-molecule inhibitor screen to identify mechanisms of sickle hemoglobin clearance by liver endothelium.

ABSTRACT: Intrahepatic accumulation of cell-free hemoglobin (Hb) is a significant pathology linked with hemolytic disorders such as sickle cell disease (SCD). In addition to hepatic Kupffer cells, liver sinusoidal endothelial cells (LSECs) were recently reported to contribute to Hb clearance in SCD mice and patients via currently unknown endocytic mechanism. Using small-molecule inhibitors of endocytic pathway components in primary human and mouse LSECs, we show that sickle-Hb (HbS) uptake by LSECs occurs predominantly through micropinocytosis or fluid-phase endocytosis. However, inhibiting clathrin-mediated endocytosis, receptor recycling, or drop in pH also significantly attenuated HbS uptake by LSECs. LSEC-driven HbS uptake was independent of haptoglobin. Finally, we found that the presence of li

SUBMITTER: Kaminski TW 

PROVIDER: S-EPMC12143466 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature