New insights into the multifaceted role of eryptosis in metabolic and cardiovascular diseases.

Cardiovascular diseases (CVDs) remain a global medical and social burden with high morbidity and mortality rates worldwide. CVDs are strongly linked to thrombosis, anemia, endothelial dysfunction, or inflammation. A growing body of evidence indicates that eryptosis, a regulated cell death of mature erythrocytes, plays an emerging role in CVDs by contributing to the above-mentioned pathogenetic links. In this review, we summarize the current knowledge of the key signaling pathways involved in eryptosis execution, highlight the pathophysiological role of eryptosis in CVDs and related metabolic disorders (including metabolic syndrome, diabetes mellitus, atherosclerosis, ischemic heart disease, or heart failure), identify the key molecular drivers of eryptosis in cardiovascular pathology, and shed light on the potential detrimental effects of enhanced eryptosis in CVDs. Identification of eryptosis-related complications of CVDs might provide novel insights into preventive and therapeutic strategies. Enhanced eryptosis in metabolic and cardiovascular pathology contributes to anemia via the accelerated clearance of eryptotic red blood cells (RBCs). Thrombogenic effects of eryptosis in CVDs are mediated by phosphatidylserine (PS)-mediated thrombin generation, interactions with platelets, and generation of coagulation-promoting PS-expressing RBC-derived microvesicles. Eryptosis-induced endothelial dysfunction is at least partly attributed to PS/CXCL16-mediated adhesion of eryptotic cells to endothelial cells (ECs), consequent uptake of eryptotic cells by ECs, and induction of their ferroptosis. On the other hand, enhanced eryptosis might have a dual role in the regulation of inflammation in CVDs. Phagocytosis of eryptotic cells reprograms macrophages to gain the pro-resolution phenotype. However, eryptosis triggers pro-inflammatory ferroptosis of ECs and immune cells at the same time.