The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling.

Although thrombosis has been extensively studied using various animal models, our understanding of the underlying mechanism remains elusive. Here, using zebrafish model, we demonstrated that -deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus. We further used the anti-thrombosis drugs to treat embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in . To explore the regulatory mechanism of in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from and their siblings and found that both the chromatin accessibility at the promoter and expression of were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of , a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon deletion. Importantly, overexpression of or knockdown of partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the RBC aggregation in mutants. Together, our study using zebrafish mutants characterizes a novel role for in RBC aggregation, which may provide a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.