Suicidal erythrocyte death or eryptosis is characterized by erythrocyte shrinkage, cell membrane blebbing, and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca2+entry, ceramide formation, stimulation of caspases, calpain activation, energy depletion, oxidative stress, and dysregulation of several kinases. Eryptosis is triggered by a wide variety of xenobiotics. It is inhibited by several xenobiotics and endogenous molecules including NO and erythropoietin. The susceptibility of erythrocytes to eryptosis increases with erythrocyte age. Phosphatidylserine exposing erythrocytes adhere to the vascular wall by binding to endothelial CXC-Motiv-Chemokin-16/Scavenger-receptor for phosphatidylserine and oxidized low density lipoprotein (CXCL16). Phosphatidylserine exposing erythrocytes are further engulfed by phagocytosing cells and are thus rapidly cleared from circulating blood. Eryptosis eliminates infected or defective erythrocytes thus counteracting parasitemia in malaria and preventing detrimental hemolysis of defective cells. Excessive eryptosis, however, may lead to anemia and may interfere with microcirculation. Enhanced eryptosis contributes to the pathophysiology of several clinical disorders including metabolic syndrome and diabetes, malignancy, cardiac and renal insufficiency, hemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose 6-phosphate dehydrogenase deficiency, and Wilson’s disease. Facilitating or inhibiting eryptosis may be a therapeutic option in those disorders. pmc-status-qastatus 0 pmc-status-live yes pmc-status-embargo no pmc-status-released yes pmc-prop-open-access yes pmc-prop-olf no pmc-prop-manuscript no pmc-prop-legally-suppressed no The increase in [Ca 2+ ] i and eryptosis following Cl − removal were thus blunted in erythrocytes from gene-targeted mice lacking TRPC6 [ 26 ]. The increase of [Ca 2+ ] i following activation of the cation channels is followed by cell shrinkage due to activation of Ca 2+ -sensitive K + channels [ 41 , 42 ], cell membrane hyperpolarization, increase in the electrical driving force for Cl − exit, and the cellular loss of KCl with osmotically obliged water [ 43 ]. The Cl − exit requires erythrocyte Cl − channels [ 44 ], which are activated by oxidative stress [ 45 , 46 ]. Unlike in apoptosis of nucleated cells, caspases do not play a dominant role in the triggering of eryptosis. Survival of erythrocytes does require the activity of several kinases including AMPK and cGKI. Activation of other kinases, such as CK1 α and JAK3, triggers eryptosis. The phosphorylation targets of the kinases required for the stimulation or inhibition of eryptosis are still ill-defined. Clearly, tremendous additional experimental effort is required for full understanding of the eryptotic machinery. 4. Phosphatidylserine-exposing erythrocytes further adhere to the vascular wall by binding of phosphatidylserine to endothelial CXC-Motiv-Chemokin-16/Scavenger receptor for phosphatidylserine and oxidized low density lipoprotein (CXCL16/SR-PSOX) [ 252 ]. Further structures binding phosphatidylserine-exposing erythrocytes include the heparin-binding domain [ 253 ] of endothelial or subendothelial thrombospondin-1 (TSP) [ 254 ] or endothelial phosphatidylserine receptors [ 255 ]. The effect is compounded by cytostatic treatment, as a wide variety of cytostatic drugs do not only trigger apoptosis of tumor cells but as well suicidal death of erythrocytes ( Table 1 ). The percentage of phosphatidylserine-exposing erythrocytes in circulating blood is increased in diabetic patients [ 120 , 224 , 260 ]. Eryptosis is stimulated by methylglyoxal [ 120 ], which accumulates in hyperglycemia [ 261 ]. Methylglyoxal is at least partially effective by interference with glycolysis and by decrease of ATP and GSH concentrations [ 120 ]. HbF may, however, sensitize erythrocytes to oxidative stress-induced eryptosis (see Section 2 ), which may, at least in theory, limit the therapeutic benefit of hydroxyurea. Heterozygous carriers of the genetic disorders, such as heterozygous sickle cell carriers (HbA/S), do not spontaneously become suicidal and the respective individuals are virtually healthy [ 281 ]. Nevertheless, the erythrocytes are more sensitive to the eryptotic effects of oxidative stress [ 281 ]. The pathogen sequesters Ca 2+ thus slowing the increase of [Ca 2+ ] i [ 296 ]. The pathogen further digests hemoglobin and exports the respective amino acids [ 297 ]. Plasmodium falciparum infection eventually leads to cell membrane scrambling with exposure of phosphatidylserine [ 105 , 294 , 298 , 299 ] and subsequent phagocytotic clearance of pathogen-containing erythrocytes [ 300 , 301 ]. The pathogen may further foster erythrocyte senescence contributing to the clearance of infected cells [ 301 , 302 ]. Importantly, the pathogen should be unable to become resistant to therapeutic acceleration of eryptosis, which depends on host cell mechanisms and is thus not at the genetic disposal of the pathogen. Along those lines, the pathogen remained unable to overcome the relative resistance of sickle cell trait carriers to malaria. 6. Conclusions Similar to apoptosis of nucleated cells, eryptosis is a physiological mechanism eliminating defective erythrocytes in order to prevent hemolysis and subsequent release of hemoglobin into circulating blood. Excessive eryptosis may, however, cause anemia and impede microcirculation. Orchestration of eryptosis involves Ca 2+ -permeable unselective cation channels, ceramide, caspases, and a variety of kinases including Janus-activated kinase 3, AMP-activated kinase, cGMP-dependent protein kinase, casein kinase 1 α , p38 kinase, protein kinase C, and p21-activated kinase 2. The sensitivity to eryptosis is enhanced in aged erythrocytes. Fetal erythrocytes are particularly sensitive to oxidative stress.