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Erythrocyte Cell Death: Molecular Insights

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 4666

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Dr. Anton Tkachenko

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BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 25250 Vestec, Czech Republic
Interests: regulated cell death; eryptosis; cancer cell biology; nanotoxicity; nanomaterials
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Dear Colleagues,

A growing body of evidence suggests that erythrocytes can undergo regulated cell death (RCD) modalities similar to apoptosis and necroptosis of nucleated cells. To emphasize the differences between these RCDs in mature erythrocytes and nucleated cells, the terms eryptosis and erythronecroptosis were introduced. Recent advances in the field have significantly expanded our knowledge on the cell death machinery of mature erythrocytes. However, additional studies could provide novel insights into the molecular mechanisms governing cell death pathways in mature erythrocytes. Accumulating evidence indicates that accelerated eryptosis is observed in multiple diseases, which can result in anemia and thrombosis development. The possibility to target eryptosis pharmaceutically is still under investigation. The search for novel molecular pathways involved in initiation and execution of eryptosis and elucidation of the crosstalk between eryptosis and necroptosis in mature erythrocytes might reveal novel targets for therapeutic interventions in eryptosis-related diseases. The Special Issue will focus on the mechanisms regulating RCD modalities in mature erythrocytes, and the studies aiming to clarify them will be gladly welcomed.

Dr. Anton Tkachenko
Guest Editor

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Keywords

cell death signaling
eryptosis
erythrocyte senescence
erythrocytes
necroptosis
regulated cell death

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Published Papers (4 papers)

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Research

15 pages, 2636 KB

Open AccessArticle

Arresting the Activity of Bacterial β-Barrel Pore-Forming Toxins by Cysteine Insertion Mutagenesis in the Homologous Region

by Alexander V. Siunov, Bogdan S. Melnik, Alexey S. Nagel, Zhanna I. Andreeva-Kovalevskaya, Natalia V. Rudenko, Anna P. Karatovskaya, Olesya S. Vetrova, Anna V. Zamyatina, Fedor A. Brovko and Alexander S. Solonin

Int. J. Mol. Sci. 2026, 27(8), 3590; https://doi.org/10.3390/ijms27083590 - 17 Apr 2026

Abstract

Bacterial β-barrel pore-forming toxins, including Staphylococcus aureus α-toxin (Hla) and Bacillus cereus toxins hemolysin II (HlyII) and cytolytic toxin K2 (CytK-2), are secreted by bacterial cells as water-soluble monomers. These monomers assemble within lipid bilayers to form cylindrical pores, leading to lysis of target eukaryotic cells. We created mutant forms of these toxins that, based on the results of X-ray structural analysis of Hla and the prediction of the 3D structure of HlyII and CytK2, can form intramolecular disulfide bonds in monomers. The substitutions were made in the region responsible for toxin insertion into the target membrane. The mutant forms reversibly altered their hemolytic activity depending on the presence of reducing reagents and were non-toxic when injected into experimental animals. The immune response to injection of the mutant forms of Hla and CytK-2 toxins resulted in higher antibody titers against the wild-type toxins and a higher level of immunological memory than with injection of the HlyII mutant. The mutant form of CytK-2 demonstrates the properties of a prototype vaccine, as immunization with this protein protects animals against the effects of the wild-type toxin. Full article

(This article belongs to the Special Issue Erythrocyte Cell Death: Molecular Insights)

19 pages, 3255 KB

Open AccessArticle

Glowing Spicules and Structural Collapse: A Single-Cell Insight into the Oxidative Aging of Favism Erythrocytes

by Giovanni Longo, Simone Dinarelli and Marco Girasole

Int. J. Mol. Sci. 2026, 27(3), 1132; https://doi.org/10.3390/ijms27031132 - 23 Jan 2026

Viewed by 375

Abstract

Erythrocyte aging is a fundamental physiological phenomenon that involves significant structural and nanomechanical alterations of the cells’ structure and function. Coupling optical, fluorescence, and Atomic Force Microscopy (AFM), we analyzed morphology, membrane roughness and nanomechanical properties of the very same RBCs arising from favism subjects, measured at different stages of their aging in vitro. We also investigated the evolution and abundance of vesicles arising from the cells over their senescence pathway. This approach combines high-resolution fluorescence imaging with the correlation of membrane topology and biomechanics. This explores the differences between investigation based on statistical morphometric parameters, such as membrane roughness, and those based on the measure of point-dependent nanomechanical properties. Our ultra-morphological study evidences the existence of clear differences in the aging of normal and favism erythrocytes that results in a larger number of cells with abnormal shapes and in a hyper-production of vesicles along the senescence pathway of favism cells. In explaining these differences, we focused on the roles played by the hemoglobin evolution and by the morpho-mechanical properties that are responsible for the skeletal alterations. In particular, our data reported evidence that the two corresponding degradative pathways are coupled and play an important enhancement role in promoting the progression of cell senescence. Full article

(This article belongs to the Special Issue Erythrocyte Cell Death: Molecular Insights)

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18 pages, 12289 KB

Open AccessArticle

Mn₃O₄ Nanocrystal-Induced Eryptosis Features Ca²⁺ Overload, ROS and RNS Accumulation, Calpain Activation, Recruitment of Caspases, and Changes in the Lipid Order of Cell Membranes

by Yuriy Kot, Volodymyr Prokopiuk, Vladimir Klochkov, Liliya Tryfonyuk, Pavel Maksimchuk, Andrey Aslanov, Kateryna Kot, Oleg Avrunin, Lesya Demchenko, Saulesh Kurmangaliyeva, Anatolii Onishchenko, Svetlana Yefimova, Ondrej Havranek and Anton Tkachenko

Int. J. Mol. Sci. 2025, 26(7), 3284; https://doi.org/10.3390/ijms26073284 - 1 Apr 2025

Cited by 2 | Viewed by 1501

Abstract

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. Full article

(This article belongs to the Special Issue Erythrocyte Cell Death: Molecular Insights)

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18 pages, 9624 KB

Open AccessArticle

Galangin Triggers Eryptosis and Hemolysis Through Ca²⁺ Nucleation and Metabolic Collapse Mediated by PKC/CK1α/COX/p38/Rac1 Signaling Axis

by Mohammad A. Alfhili, Sumiah A. Alghareeb, Ghada A. Alotaibi and Jawaher Alsughayyir

Int. J. Mol. Sci. 2024, 25(22), 12267; https://doi.org/10.3390/ijms252212267 - 15 Nov 2024

Cited by 3 | Viewed by 1826

Abstract

Anticancer drugs cause anemia in patients through eryptosis and hemolysis. We thus studied the in vitro toxicity of galangin (GAL) in red blood cells (RBCs). RBCs were exposed to 50–500 μM of GAL and analyzed for markers of eryptosis and hemolysis. Ca²⁺ nucleation, phosphatidylserine (PS) externalization, oxidative stress, and cell size were detected via fluorescence-activated cell sorting using Fluo4/AM, annexin-V-FITC, 2′,7′-dichlorodihydrofluorescein diacetate, and forward scatter (FSC), respectively. Acetylcholinesterase (AChE) activity was measured via Ellman’s assay and ultrastructural morphology was examined via scanning electron microscopy. Membrane rupture and extracellular hemoglobin, aspartate transaminase (AST), and lactate dehydrogenase (LDH) were assessed via colorimetric methods. Distinct experiments were carried out to identify protective agents and signaling pathways using small-molecule inhibitors. GAL triggered sucrose-sensitive hemolysis with AST and LDH leakage, increased annexin-V-FITC and Fluo4 fluorescence, and decreased FSC and AChE activity which was associated with the formation of granulated echinocytes. Ca²⁺ omission and energy replenishment with glucose, adenine, and guanosine blunted PS externalization and preserved cellular volume. Moreover, caffeine, Trolox, heparin, and uric acid had similar ameliorative effects. Hemolysis was abrogated via caffeine, Trolox, heparin, mannitol, lactate, melatonin, and PEG 8000. Notably, co-treatment of cells with GAL and staurosporin, D4476, or acetylsalicylic acid prevented PS externalization whereas only the presence of SB203580 and NSC23766 rescued the cells from GAL-induced hemolysis. Ca²⁺ nucleation and metabolic collapse mediated by PKC/CK1α/COX/p38/Rac1 drive GAL-induced eryptosis and hemolysis. These novel findings carry ramifications for the clinical prospects of GAL in anticancer therapy. Full article

(This article belongs to the Special Issue Erythrocyte Cell Death: Molecular Insights)

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