Eryptosis is a type of regulated cell death of mature erythrocytes characterized by excessive Ca2+ accumulation followed by phosphatidylserine externalization. Eryptosis facilitates erythrophagocytosis resulting in eradication of damaged erythrocytes, which maintains the population of healthy erythrocytes in blood. Over recent years, a wide array of diseases has been reported to be linked to accelerated eryptosis, which leads to anemia. A growing number of studies furnish evidence that eryptosis is implicated in the pathogenesis of liver diseases. Herein, we summarize the current knowledge of eryptosis signaling, its physiological role, and the impact of eryptosis on anemia and hypercoagulation. In this article, upon systemically analyzing the PubMed-indexed publications, we also provide a comprehensive overview of the role of eryptosis in the spectrum of hepatic diseases, its contribution to the development of complications in liver pathology, metabolites (bilirubin, bile acids, etc.) that might trigger eryptosis in liver diseases, and eryptosis-inducing liver disease medications. Eryptosis in liver diseases contributes to anemia, hypercoagulation, and endothelial damage (via ferroptosis of endothelial cells). Treatment-associated anemia in liver diseases might be at least partly attributed to drug-induced eryptosis. Ultimately, we analyze the concept of inhibiting eryptosis pharmaceutically to prevent eryptosis-associated anemia and thrombosis in liver diseases.

• Keywords
• bile acids, bilirubin, chronic liver disease, eryptosis, non-alcoholic fatty liver disease, regulated cell death,
• MeSH
• Anemia * pathology   etiology   MeSH
• Eryptosis * physiology   MeSH
• Erythrocytes pathology   metabolism   MeSH
• Humans MeSH
• Liver Diseases * complications   pathology   blood   MeSH
• Thrombophilia * etiology   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

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.

• MeSH
• Apoptosis MeSH
• Eryptosis * drug effects   physiology   MeSH
• Erythrocytes * metabolism   drug effects   cytology   MeSH
• Humans MeSH
• Terminology as Topic MeSH
• Calcium metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Calcium MeSH

Accumulating evidence suggests that manganese oxide nanoparticles (NPs) show multiple enzyme-mimicking antioxidant activities, which supports their potential in redox-targeting therapeutic strategies for diseases with impaired redox signaling. However, the systemic administration of any NP requires thorough hemocompatibility testing. In this study, we assessed the hemocompatibility of synthesized Mn3O4 NPs, identifying their ability to induce spontaneous hemolysis and eryptosis or impair osmotic fragility. Concentrations of up to 20 mg/L were found to be safe for erythrocytes. Eryptosis assays were shown to be more sensitive than hemolysis and osmotic fragility as markers of hemocompatibility for Mn3O4 NP testing. Flow cytometry- and confocal microscopy-based studies revealed that eryptosis induced by Mn3O4 NPs was accompanied by Ca2+ overload, altered redox homeostasis verified by enhanced intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS), and a decrease in the lipid order of cell membranes. Furthermore, Mn3O4 NP-induced eryptosis was calpain- and caspase-dependent.

• Keywords
• calcium signaling, cytotoxicity, eryptosis, nanoparticles, oxidative stress, regulated cell death,
• MeSH
• Cell Membrane * metabolism   drug effects   MeSH
• Eryptosis * drug effects   MeSH
• Erythrocytes drug effects   metabolism   MeSH
• Hemolysis drug effects   MeSH
• Calpain * metabolism   MeSH
• Caspases * metabolism   MeSH
• Humans MeSH
• Nanoparticles * chemistry   MeSH
• Oxides * pharmacology   chemistry   MeSH
• Reactive Nitrogen Species * metabolism   MeSH
• Reactive Oxygen Species * metabolism   MeSH
• Manganese Compounds * pharmacology   chemistry   MeSH
• Calcium * metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Calpain * MeSH
• Caspases * MeSH
• manganese oxide MeSH Browser
• Oxides * MeSH
• Reactive Nitrogen Species * MeSH
• Reactive Oxygen Species * MeSH
• Manganese Compounds * MeSH
• Calcium * MeSH

Over the recent years, our understanding of the cell death machinery of mature erythrocytes has been greatly expanded. It resulted in the discovery of several regulated cell death (RCD) pathways in red blood cells. Apoptosis (eryptosis) and necroptosis of erythrocytes share certain features with their counterparts in nucleated cells, but they are also critically different in particular details. In this review article, we summarize the cell death subroutines in the erythroid precursors (apoptosis, necroptosis, and ferroptosis) in comparison to mature erythrocytes (eryptosis and erythronecroptosis) to highlight the consequences of organelle clearance and associated loss of multiple components of the cell death machinery upon erythrocyte maturation. Recent advances in understanding the role of erythrocyte RCDs in health and disease have expanded potential clinical applications of these lethal subroutines, emphasizing their contribution to the development of anemia, microthrombosis, and endothelial dysfunction, as well as their role as diagnostic biomarkers and markers of erythrocyte storage-induced lesions. Fas signaling and the functional caspase-8/caspase-3 system are not indispensable for eryptosis, but might be retained in mature erythrocytes to mediate the crosstalk between both erythrocyte-associated RCDs. The ability of erythrocytes to switch between eryptosis and necroptosis suggests that their cell death is not a simple unregulated mechanical disintegration, but a tightly controlled process. This allows investigation of eventual pharmacological interventions aimed at individual cell death subroutines of erythrocytes.

• Keywords
• Apoptosis, Cell death, Ferroptosis, Necroptosis, Red blood cell,
• MeSH
• Apoptosis * MeSH
• Cell Death MeSH
• Eryptosis MeSH
• Erythrocytes * metabolism   cytology   MeSH
• Ferroptosis MeSH
• Humans MeSH
• Necroptosis MeSH
• Signal Transduction * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH