Current understanding of eryptosis: mechanisms, physiological functions, role in disease, pharmacological applications, and nomenclature recommendations

Abstract

Early studies have shown that erythrocytes have caspase-3 and caspase-8 and are capable of dying through an apoptotic-like cell death triggered by Ca²⁺ ionophores. This cell death is associated with apoptosis-like morphological signs, including cell shrinkage, membrane blebbing, and phosphatidylserine externalization. To emphasize that mature erythrocytes don't have the apoptotic mitochondrial machinery and distinguish this unique cell death modality from apoptosis, it was named "eryptosis". Over recent decades, our knowledge of eryptosis has been significantly expanded, providing more insights into the uniqueness of cell death pathways in erythrocytes. In this review, we aim to summarize our current understanding of eryptosis, formulate the nomenclature and guidelines to interpret results of eryptosis studies, provide a synopsis of morphological and biochemical features of eryptosis, and highlight the role of eryptosis in health and disease, including its druggability.

Fig. 1. The set of cell death modalities is scarce is mature erythrocytes.

Accidental and regulated cell death modalities in nucleated cells (a) and mature erythrocytes (b). Lack of organelles in mature erythrocytes restricts the diversity of the cell death machinery. ACDC autophagy-dependent cell death, PARP poly (ADP-ribose) polymerase, ROS reactive oxygen species. Created with Biorender.com.

Fig. 2. Eryptosis is a calcium-mediated, regulated cell death of erythrocytes associated with cell shrinkage, membrane microvesiculation, and phosphatidylserine exposure, resulting in efferocytosis, the phosphatidylserine-mediated clearance of eryptotic erythrocytes by macrophages.

cGKI cGMP-dependent protein kinase I, CK1α casein kinase 1α, FADD Fas-associated death domain, p38 MAPK p38 mitogen-activated protein kinase, PGE₂ prostaglandin E2, PKC protein kinase C, PS phosphatidylserine, RNS reactive nitrogen species, ROS reactive oxygen species, SM acid and neutral sphingomyelin, SMases acid and neutral sphingomyelinases. Created with Biorender.com.

Fig. 3. Eryptosis prevents hemolysis and ensures the clearance of damaged red blood cells.

Hemolysis is associated with the release of DAMPs, which in turn can promote the innate immune response. Furthermore, eryptosis facilitates the elimination of P. falciparum-infected erythrocytes. DAMPs damage-associated molecular patterns. Created with Biorender.com.

Fig. 4. Enhanced eryptosis may lead to excessive clearance of eryptotic erythrocytes, resulting in anemia, promotion of blood clotting via phosphatidylserine-mediated mechanisms, and endothelial dysfunction associated with injury of endothelial cells.

Created with Biorender.com.

Fig. 5. Long COVID is associated with circulating inflammatory molecules that contribute to endothelialitis, microclot formation, platelet hyperactivity, and damage to erythrocytes, which may impair blood rheology and result in inadequate microcirculation, leading to ischemia-reperfusion injury (above).

Scanning electron microscopy shows erythrocytes from Long COVID patients are covered by fibrin amyloid microclots (below). Created with Biorender.com.

Fig. 6. Multiple nanomaterials trigger Ca²⁺-dependent eryptosis primarily via ROS-mediated signaling.

Eryptosis can be induced by both internalized and non-internalized nanomaterials. Nanomaterial-induced eryptosis might be mediated by caspase-3 and calpain. CAT catalase, CTAB cetyltrimethylammonium bromide, D-PAA dextran-polyacrylamide, NPs nanoparticles, PLGA poly(lactic-co-glycolic acid), PS phosphatidylserine, PVP polyvinylpyrrolidone, ROS reactive oxygen species, SOD superoxide dismutase. Created with Biorender.com.