In response to acute stress, nucleated cells undergo various regulated cell deaths (RCDs). Alternatively and in the long run, they permanently stop proliferating with the parallel acquisition of apoptosis resistance and the senescence-associated secretory phenotype. This particular long-term stress response is referred to as cellular senescence. Terminally differentiated, anucleate red blood cells (RBCs) cannot proliferate anymore and are incapable of synthesizing proteins. RBC senescence is therefore defined by phagocytosis-promoting age-related changes, such as band 3 protein-derived senescent erythrocyte-specific antigen (SESA)-mediated binding of autologous antibodies, desialylated glycoproteins, CD47 loss, and glycophorin depletion. Additionally, RBCs can undergo eryptosis, a Ca2+-driven RCD. Here, we consider the intracellular signals that drive RBC senescence and eryptosis to underscore how these pathways are intertwined. Our findings suggest that RBC senescence and eryptosis are distinct processes with their differences primarily lying in how fast senescent and eryptotic RBCs are removed from the circulation. Severe damage to RBCs promotes intense Ca2+ influx, oxidative and nitrosative stress, as well as activation of caspase-3. This eventually leads to phosphatidylserine externalization and eryptosis. Phosphatidylserine externalization, in turn, ensures swift erythrophagocytosis of eryptotic RBCs thus preventing hemolysis. On the other hand, suberyptotic stress stimuli are not sufficient to trigger rapid cell death. However, they mediate the gradual and inevitable accumulation of senescence-associated injuries. Clearance of senescent RBCs with low-level phosphatidylserine exposure is slow-paced, and mature RBCs possess mechanisms to eradicate senescence markers that tag cells for phagocytosis to extend their lifespan (e.g., generation of vesicles). In this review, we highlight the physiological significance of RBC senescence and eryptosis, and provide practical guidelines to distinguish them thus avoiding misinterpretation of experimental data.

BIOCEV 1st Faculty of Medicine Charles University Průmyslová 595 25250 Vestec Czech Republic

Department of Hematology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Institute of Immunology University of Duisburg Essen Hufelandstr 55 45147 Essen Germany

Institute of Physiology 1 Eberhard Karls University Tübingen Wilhelmstr 56 72074 Tübingen Germany

Zobrazit více v PubMed

Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 2015;22(1):58–73. https://doi.org/10.1038/cdd.2014.137 . PubMed DOI

Galluzzi L, Bravo-San Pedro JM, Kepp O, Kroemer G. Regulated cell death and adaptive stress responses. Cell Mol Life Sci. 2016;73(11–12):2405–10. https://doi.org/10.1007/s00018-016-2209-y . PubMed DOI PMC

Kist M, Vucic D. Cell death pathways: intricate connections and disease implications. EMBO J. 2021;40(5):e106700. https://doi.org/10.15252/embj.2020106700 . PubMed DOI PMC

Zhou L, Sun J, Gu L, Wang S, Yang T, Wei T, et al. Programmed cell death: complex regulatory networks in cardiovascular disease. Front Cell Dev Biol. 2021;9:794879. https://doi.org/10.3389/fcell.2021.794879 . PubMed DOI PMC

Lee E, Song C-H, Bae S-J, Ha K-T, Karki R. Regulated cell death pathways and their roles in homeostasis, infection, inflammation, and tumorigenesis. Exp Mol Med. 2023;55(8):1632–43. https://doi.org/10.1038/s12276-023-01069-y . PubMed DOI PMC

Pignolo RJ, Passos JF, Khosla S, Tchkonia T, Kirkland JL. Reducing senescent cell burden in aging and disease. Trends Mol Med. 2020;26(7):630–8. https://doi.org/10.1016/j.molmed.2020.03.005 . PubMed DOI PMC

Galluzzi L, Myint M. Cell death and senescence. J Transl Med. 2023;21(1):425. https://doi.org/10.1186/s12967-023-04297-y . PubMed DOI PMC

Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, et al. T-helper-1-cell cytokines drive cancer into senescence. Nature. 2013;494(7437):361–5. https://doi.org/10.1038/nature11824 . PubMed DOI

Benhamed M, Herbig U, Ye T, Dejean A, Bischof O. Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells. Nat Cell Biol. 2012;14(3):266–75. https://doi.org/10.1038/ncb2443 . PubMed DOI PMC

Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486–541. https://doi.org/10.1038/s41418-017-0012-4 . PubMed DOI PMC

Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118. https://doi.org/10.1146/annurev-pathol-121808-102144 . PubMed DOI PMC

Lopes-Paciencia S, Saint-Germain E, Rowell M-C, Ruiz AF, Kalegari P, Ferbeyre G. The senescence-associated secretory phenotype and its regulation. Cytokine. 2019;117:15–22. https://doi.org/10.1016/j.cyto.2019.01.013 . PubMed DOI

Wang B, Han J, Elisseeff JH, Demaria M. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol. 2024. https://doi.org/10.1038/s41580-024-00727-x . PubMed DOI

Kumari R, Jat P. Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Front Cell Dev Biol. 2021. https://doi.org/10.3389/fcell.2021.645593 . PubMed DOI PMC

Ohtani N. The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis? Inflamm Regen. 2022;42(1):11. https://doi.org/10.1186/s41232-022-00197-8 . PubMed DOI PMC

Cuollo L, Antonangeli F, Santoni A, Soriani A. The senescence-associated secretory phenotype (SASP) in the challenging future of cancer therapy and age-related diseases. Biology. 2020;9(12):485. PubMed DOI PMC

Huang W, Hickson LJ, Eirin A, Kirkland JL, Lerman LO. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol. 2022;18(10):611–27. https://doi.org/10.1038/s41581-022-00601-z . PubMed DOI PMC

McHugh D, Durán I, Gil J. Senescence as a therapeutic target in cancer and age-related diseases. Nat Rev Drug Discov. 2025;24(1):57–71. https://doi.org/10.1038/s41573-024-01074-4 . PubMed DOI

Campisi J. Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes. Exp Gerontol. 2003;38(1):5–11. https://doi.org/10.1016/S0531-5565(02)00152-3 . PubMed DOI

Childs BG, Baker DJ, Kirkland JL, Campisi J, van Deursen JM. Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep. 2014;15(11):1139–53. https://doi.org/10.15252/embr.201439245 . PubMed DOI PMC

Hu L, Li H, Zi M, Li W, Liu J, Yang Y, et al. Why senescent cells are resistant to apoptosis: an insight for senolytic development. Front Cell Dev Biol. 2022. https://doi.org/10.3389/fcell.2022.822816 . PubMed DOI PMC

Basu A. The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy. Pharmacol Ther. 2022;230:107943. https://doi.org/10.1016/j.pharmthera.2021.107943 . PubMed DOI

Lutz HU, Bogdanova A. Mechanisms tagging senescent red blood cells for clearance in healthy humans. Front Physiol. 2013;4:387. https://doi.org/10.3389/fphys.2013.00387 . PubMed DOI PMC

Tkachenko A, Havranek O. Erythronecroptosis: an overview of necroptosis or programmed necrosis in red blood cells. Mol Cell Biochem. 2024. https://doi.org/10.1007/s11010-024-04948-8 . PubMed DOI

Tkachenko A, Havránek O. Redox status of erythrocytes as an important factor in eryptosis and erythronecroptosis. Folia Biol Praha. 2023;69(4):116–26. https://doi.org/10.14712/fb2023069040116 . PubMed DOI

Tkachenko A. Apoptosis and eryptosis: similarities and differences. Apoptosis. 2024;29(3–4):482–502. https://doi.org/10.1007/s10495-023-01915-4 . PubMed DOI

Tkachenko A, Havranek O. Cell death signaling in human erythron: erythrocytes lose the complexity of cell death machinery upon maturation. Apoptosis. 2025. https://doi.org/10.1007/s10495-025-02081-5 . PubMed DOI PMC

Bosman GJ, Willekens FL, Werre JM. Erythrocyte aging: a more than superficial resemblance to apoptosis? Cell Physiol Biochem. 2005;16(1–3):1–8. https://doi.org/10.1159/000087725 . PubMed DOI

Badior KE, Casey JR. Molecular mechanism for the red blood cell senescence clock. IUBMB Life. 2018;70(1):32–40. https://doi.org/10.1002/iub.1703 . PubMed DOI

Maruyama T, Fukata M, Fujino T. Physiological and pathophysiological significance of erythrocyte senescence, density and deformability: important but unnoticed trinity. J Biorheol. 2020;34(2):61–70. https://doi.org/10.17106/jbr.34.61 . DOI

Neu B, Sowemimo-Coker SO, Meiselman HJ. Cell-cell affinity of senescent human erythrocytes. Biophys J. 2003;85(1):75–84. https://doi.org/10.1016/S0006-3495(03)74456-7 . PubMed DOI PMC

Chen LY, Chen PL, Jiang ST, Lee HL, Liu YY, Chueh A, et al. Increased anion exchanger-1 (band 3) on the red blood cell membrane accelerates scavenging of nitric oxide metabolites and predisposes hypertension risks. Function. 2025. https://doi.org/10.1093/function/zqae052 . PubMed DOI

Kay MM. Isolation of the phagocytosis-inducing IgG-binding antigen on senescent somatic cells. Nature. 1981;289(5797):491–4. https://doi.org/10.1038/289491a0 . PubMed DOI

Kriebardis AG, Antonelou MH, Stamoulis KE, Economou-Petersen E, Margaritis LH, Papassideri IS. Storage-dependent remodeling of the red blood cell membrane is associated with increased immunoglobulin G binding, lipid raft rearrangement, and caspase activation. Transfusion. 2007;47(7):1212–20. https://doi.org/10.1111/j.1537-2995.2007.01254.x . PubMed DOI

Remigante A, Morabito R, Marino A. Band 3 protein function and oxidative stress in erythrocytes. J Cell Physiol. 2021;236(9):6225–34. https://doi.org/10.1002/jcp.30322 . PubMed DOI

Ando K, Beppu M, Kikugawa K, Hamasaki N. Increased susceptibility of stored erythrocytes to anti-band 3 IgG autoantibody binding. Biochim Biophys Acta. 1993;1178(2):127–34. https://doi.org/10.1016/0167-4889(93)90002-7 . PubMed DOI

Arese P, Gallo V, Pantaleo A, Turrini F. Life and death of glucose-6-phosphate dehydrogenase (G6PD) deficient erythrocytes - role of redox stress and band 3 modifications. Transfus Med Hemother. 2012;39(5):328–34. https://doi.org/10.1159/000343123 . PubMed DOI PMC

Rossi V, Leoncini S, Signorini C, Buonocore G, Paffetti P, Tanganelli D, et al. Oxidative stress and autologous immunoglobulin G binding to band 3 dimers in newborn erythrocytes. Free Radic Biol Med. 2006;40(5):907–15. https://doi.org/10.1016/j.freeradbiomed.2005.11.021 . PubMed DOI

Bloch EM, Branch HA, Sakac D, Leger RM, Branch DR. Differential red blood cell age fractionation and band 3 phosphorylation distinguish two different subtypes of warm autoimmune hemolytic anemia. Transfusion. 2020;60(8):1856–66. https://doi.org/10.1111/trf.15911 . PubMed DOI

Ciccoli L, Rossi V, Leoncini S, Signorini C, Blanco-Garcia J, Aldinucci C, et al. Iron release, superoxide production and binding of autologous IgG to band 3 dimers in newborn and adult erythrocytes exposed to hypoxia and hypoxia-reoxygenation. Biochimica et Biophysica Acta (BBA) - General Subjects. 2004;1672(3):203–13. https://doi.org/10.1016/j.bbagen.2004.04.003 . PubMed DOI

Yang H, Xun Y, You H. The landscape overview of CD47-based immunotherapy for hematological malignancies. Biomark Res. 2023;11(1):15. https://doi.org/10.1186/s40364-023-00456-x . PubMed DOI PMC

Maute R, Xu J, Weissman IL. CD47-SIRPα-targeted therapeutics: status and prospects. Immuno-Oncology and Technology. 2022;13:100070. https://doi.org/10.1016/j.iotech.2022.100070 . DOI PMC

Oldenborg PA, Zheleznyak A, Fang YF, Lagenaur CF, Gresham HD, Lindberg FP. Role of CD47 as a marker of self on red blood cells. Science. 2000;288(5473):2051–4. https://doi.org/10.1126/science.288.5473.2051 . PubMed DOI

Khandelwal S, van Rooijen N, Saxena RK. Reduced expression of CD47 during murine red blood cell (RBC) senescence and its role in RBC clearance from the circulation. Transfusion. 2007;47(9):1725–32. https://doi.org/10.1111/j.1537-2995.2007.01348.x . PubMed DOI

Olsson M, Oldenborg P-A. CD47 on experimentally senescent murine RBCs inhibits phagocytosis following Fcγ receptor–mediated but not scavenger receptor–mediated recognition by macrophages. Blood. 2008;112(10):4259–67. https://doi.org/10.1182/blood-2008-03-143008 . PubMed DOI

Burger P, de Korte D, van den Berg TK, van Bruggen R. CD47 in erythrocyte ageing and clearance - the Dutch point of view. Transfus Med Hemother. 2012;39(5):348–52. https://doi.org/10.1159/000342231 . PubMed DOI PMC

van Bruggen R. CD47 functions as a removal marker on aged erythrocytes. ISBT Sci Ser. 2013;8(1):153–6. https://doi.org/10.1111/voxs.12038 . DOI

Mordue KE, Satchwell TJ, Toye AM. CD47 is dependent on the actin cytoskeleton for its membrane stability prior to protein 4.2 expression during early erythroblast differentiation. Blood. 2014;124(21):2665. https://doi.org/10.1182/blood.V124.21.2665.2665 . DOI

Bruce LJ, Ghosh S, King MJ, Layton DM, Mawby WJ, Stewart GW, et al. Absence of CD47 in protein 4.2–deficient hereditary spherocytosis in man: an interaction between the Rh complex and the band 3 complex: presented at the 43rd Annual Meeting of the American Society of Hematology, Orlando, FL, December 7–11, 2001, and abstract published in Blood. 2001;98:(suppl1):10a. Blood. 2002;100(5):1878–85. https://doi.org/10.1182/blood-2002-03-0706

Huang YX, Tuo WW, Wang D, Kang LL, Chen XY, Luo M. Restoring the youth of aged red blood cells and extending their lifespan in circulation by remodelling membrane sialic acid. J Cell Mol Med. 2016;20(2):294–301. https://doi.org/10.1111/jcmm.12721 . PubMed DOI

Durocher JR, Payne RC, Conrad ME. Role of sialic acid in erythrocyte survival. Blood. 1975;45(1):11–20. PubMed DOI

Kumar D, Rizvi SI. Erythrocyte membrane bound and plasma sialic acid during aging. Biol. 2013;68(4):762–5. https://doi.org/10.2478/s11756-013-0207-1 . DOI

Zhu W, Zhou Y, Guo L, Feng S. Biological function of sialic acid and sialylation in human health and disease. Cell Death Discov. 2024;10(1):415. https://doi.org/10.1038/s41420-024-02180-3 . PubMed DOI PMC

Kolb-Bachofen V, Schlepper-Schäfer J, Vogell W, Kolb H. Electron microscopic evidence for an asialoglycoprotein receptor on kupffer cells: localization of lectin-mediated endocytosis. Cell. 1982;29(3):859–66. https://doi.org/10.1016/0092-8674(82)90447-0 . PubMed DOI

Spiess M, Lodish HF. An internal signal sequence: the asialoglycoprotein receptor membrane anchor. Cell. 1986;44(1):177–85. https://doi.org/10.1016/0092-8674(86)90496-4 . PubMed DOI

Kiser ZM, Lizcano A, Nguyen J, Becker GL, Belcher JD, Varki AP, et al. Decreased erythrocyte binding of Siglec-9 increases neutrophil activation in sickle cell disease. Blood Cells Mol Dis. 2020;81:102399. https://doi.org/10.1016/j.bcmd.2019.102399 . PubMed DOI

Mehdi MM, Singh P, Rizvi SI. Erythrocyte sialic acid content during aging in humans: correlation with markers of oxidative stress. Dis Markers. 2012;32(3):179–86. https://doi.org/10.3233/dma-2011-0871 . PubMed DOI PMC

Klei TRL, Dalimot JJ, Beuger BM, Veldthuis M, Ichou FA, Verkuijlen P, et al. The Gardos effect drives erythrocyte senescence and leads to Lu/BCAM and CD44 adhesion molecule activation. Blood Adv. 2020;4(24):6218–29. https://doi.org/10.1182/bloodadvances.2020003077 . PubMed DOI PMC

Joshi U, George LB, Highland H. Red blood cell extracellular vesicles: new frontiers in hematological biomarker discovery. Front Med. 2025;12:1644077. https://doi.org/10.3389/fmed.2025.1644077 . DOI

Bosman GJCGM, Lasonder E, Groenen-Döpp YAM, Willekens FLA, Werre JM. The proteome of erythrocyte-derived microparticles from plasma: new clues for erythrocyte aging and vesiculation. J Proteomics. 2012;76:203–10. https://doi.org/10.1016/j.jprot.2012.05.031 . PubMed DOI

Besedina NA, Skverchinskaya EA, Shmakov SV, Ivanov AS, Mindukshev IV, Bukatin AS. Persistent red blood cells retain their ability to move in microcapillaries under high levels of oxidative stress. Commun Biol. 2022;5(1):659. https://doi.org/10.1038/s42003-022-03620-5 . PubMed DOI PMC

Çimen MYB. Free radical metabolism in human erythrocytes. Clin Chim Acta. 2008;390(1):1–11. https://doi.org/10.1016/j.cca.2007.12.025 . PubMed DOI

Zhou W, Xu X, Qi D, Zhang X, Zheng F. Elevated mtDNA content in RBCs promotes oxidative stress may be responsible for faster senescence in men. Arch Gerontol Geriatr. 2024;125:105504. https://doi.org/10.1016/j.archger.2024.105504 . PubMed DOI

Matarrese P, Straface E, Pietraforte D, Gambardella L, Vona R, Maccaglia A, et al. Peroxynitrite induces senescence and apoptosis of red blood cells through the activation of aspartyl and cysteinyl proteases. Faseb j. 2005;19(3):416–8. https://doi.org/10.1096/fj.04-2450fje . PubMed DOI

Pietraforte D, Matarrese P, Straface E, Gambardella L, Metere A, Scorza G, et al. Two different pathways are involved in peroxynitrite-induced senescence and apoptosis of human erythrocytes. Free Radic Biol Med. 2007;42(2):202–14. https://doi.org/10.1016/j.freeradbiomed.2006.10.035 . PubMed DOI

Buerck JP, Burke DK, Schmidtke DW, Snyder TA, Papavassiliou D, O’Rear EA. A flow induced autoimmune response and accelerated senescence of red blood cells in cardiovascular devices. Sci Rep. 2019;9(1):19443. https://doi.org/10.1038/s41598-019-55924-y . PubMed DOI PMC

Gural A, Pajić-Lijaković I, Barshtein G. Mechanical stimulation of red blood cells aging: focusing on the microfluidics application. Micromachines. 2025;16(3):259. PubMed DOI PMC

Garcia-Herreros A, Yeh YT, Peng Z, Del Álamo JC. Cyclic mechanical stresses alter erythrocyte membrane composition and microstructure and trigger macrophage phagocytosis. Adv Sci Weinh. 2022;9(20):e2201481. https://doi.org/10.1002/advs.202201481 . PubMed DOI

Grau M, Kuck L, Dietz T, Bloch W, Simmonds MJ. Sub-fractions of red blood cells respond differently to shear exposure following superoxide treatment. Biol. 2021. https://doi.org/10.3390/biology10010047 . DOI

McNamee AP, Horobin JT, Tansley GD, Simmonds MJ. Oxidative stress increases erythrocyte sensitivity to shear-mediated damage. Artif Organs. 2018;42(2):184–92. https://doi.org/10.1111/aor.12997 . PubMed DOI

Domingo-Ortí I, Lamas-Domingo R, Ciudin A, Hernández C, Herance JR, Palomino-Schätzlein M, et al. Metabolic footprint of aging and obesity in red blood cells. Aging Albany NY. 2021;13(4):4850–80. https://doi.org/10.18632/aging.202693 . PubMed DOI PMC

Magnani M, Piatti E, Serafini N, Palma F, Dachà M, Fornaini G. The age-dependent metabolic decline of the red blood cell. Mech Ageing Dev. 1983;22(3–4):295–308. https://doi.org/10.1016/0047-6374(83)90084-2 . PubMed DOI

Jamshidi N, Xu X, von Löhneysen K, Soldau K, Mohney RP, Karoly ED, et al. Metabolome changes during in vivo red cell aging reveal disruption of key metabolic pathways. iScience. 2020;23(10):101630. https://doi.org/10.1016/j.isci.2020.101630 . PubMed DOI PMC

Khansari N, Shakiba Y, Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Recent Pat Inflamm Allergy Drug Discov. 2009;3(1):73–80. https://doi.org/10.2174/187221309787158371 . PubMed DOI

George A, Pushkaran S, Konstantinidis DG, Koochaki S, Malik P, Mohandas N, et al. Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood. 2013;121(11):2099–107. https://doi.org/10.1182/blood-2012-07-441188 . PubMed DOI PMC

Eriksson LB, Eriksson MB, Gordh T, Larsson AO. Significant associations between blood cell counts and plasma cytokines, chemokines, and growth factors. Int J Mol Sci. 2025. https://doi.org/10.3390/ijms26094065 . PubMed DOI PMC

Karsten E, Breen E, McCracken SA, Clarke S, Herbert BR. Red blood cells exposed to cancer cells in culture have altered cytokine profiles and immune function. Sci Rep. 2020;10(1):7727. https://doi.org/10.1038/s41598-020-64319-3 . PubMed DOI PMC

Karsten E, Herbert BR. The emerging role of red blood cells in cytokine signalling and modulating immune cells. Blood Rev. 2020;41:100644. https://doi.org/10.1016/j.blre.2019.100644 . PubMed DOI

Berg CP, Engels IH, Rothbart A, Lauber K, Renz A, Schlosser SF, et al. Human mature red blood cells express caspase-3 and caspase-8, but are devoid of mitochondrial regulators of apoptosis. Cell Death Differ. 2001;8(12):1197–206. https://doi.org/10.1038/sj.cdd.4400905 . PubMed DOI

Bratosin D, Estaquier J, Petit F, Arnoult D, Quatannens B, Tissier JP, et al. Programmed cell death in mature erythrocytes: a model for investigating death effector pathways operating in the absence of mitochondria. Cell Death Differ. 2001;8(12):1143–56. https://doi.org/10.1038/sj.cdd.4400946 . PubMed DOI

Daugas E, Candé C, Kroemer G. Erythrocytes: death of a mummy. Cell Death Differ. 2001;8(12):1131–3. https://doi.org/10.1038/sj.cdd.4400953 . PubMed DOI

Bigdelou P, Farnoud AM. Induction of eryptosis in red blood cells using a calcium ionophore. J Vis Exp. 2020(155). https://doi.org/10.3791/60659

Lang KS, Roll B, Myssina S, Schittenhelm M, Scheel-Walter HG, Kanz L, et al. Enhanced erythrocyte apoptosis in sickle cell anemia, thalassemia and glucose-6-phosphate dehydrogenase deficiency. Cell Physiol Biochem. 2002;12(5–6):365–72. https://doi.org/10.1159/000067907 . PubMed DOI

Lang KS, Duranton C, Poehlmann H, Myssina S, Bauer C, Lang F, et al. Cation channels trigger apoptotic death of erythrocytes. Cell Death Differ. 2003;10(2):249–56. https://doi.org/10.1038/sj.cdd.4401144 . PubMed DOI

Föller M, Lang F. Ion transport in eryptosis, the suicidal death of erythrocytes. Front Cell Dev Biol. 2020;8:597. https://doi.org/10.3389/fcell.2020.00597 . PubMed DOI PMC

Bialevich KI, Kostsin DG, Slobozhanina EI. Eryptosis is the programmed death of erythrocytes. Biol Bull Rev. 2014;4(6):477–83. https://doi.org/10.1134/S2079086414060024 . DOI

Lang PA, Kaiser S, Myssina S, Wieder T, Lang F, Huber SM. Role of Ca2+-activated K+ channels in human erythrocyte apoptosis. Am J Physiol Cell Physiol. 2003;285(6):C1553-60. https://doi.org/10.1152/ajpcell.00186.2003 . PubMed DOI

Wieschhaus A, Khan A, Zaidi A, Rogalin H, Hanada T, Liu F, et al. Calpain-1 knockout reveals broad effects on erythrocyte deformability and physiology. Biochem J. 2012;448(1):141–52. https://doi.org/10.1042/bj20121008 . PubMed DOI

Lang F, Lang KS, Lang PA, Huber SM, Wieder T. Mechanisms and significance of eryptosis. Antioxid Redox Signal. 2006;8(7–8):1183–92. https://doi.org/10.1089/ars.2006.8.1183 . PubMed DOI

Lang F, Qadri SM. Mechanisms and significance of eryptosis, the suicidal death of erythrocytes. Blood Purif. 2012;33(1–3):125–30. https://doi.org/10.1159/000334163 . PubMed DOI

Montigny C, Lyons J, Champeil P, Nissen P, Lenoir G. On the molecular mechanism of flippase- and scramblase-mediated phospholipid transport. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2016;1861(8):767–83. https://doi.org/10.1016/j.bbalip.2015.12.020 . PubMed DOI

Repsold L, Joubert AM. Eryptosis: an erythrocyte’s suicidal type of cell death. Biomed Res Int. 2018;2018:9405617. https://doi.org/10.1155/2018/9405617 . PubMed DOI PMC

Chang CF, Goods BA, Askenase MH, Hammond MD, Renfroe SC, Steinschneider AF, et al. Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. J Clin Invest. 2018;128(2):607–24. https://doi.org/10.1172/jci95612 . PubMed DOI

Walker B, Towhid ST, Schmid E, Hoffmann SM, Abed M, Münzer P, et al. Dynamic adhesion of eryptotic erythrocytes to immobilized platelets via platelet phosphatidylserine receptors. Am J Physiol Cell Physiol. 2014;306(3):C291–7. https://doi.org/10.1152/ajpcell.00318.2013 . PubMed DOI

Sun S, Campello E, Zou J, Konings J, Huskens D, Wan J, et al. Crucial roles of red blood cells and platelets in whole blood thrombin generation. Blood Adv. 2023;7(21):6717–31. https://doi.org/10.1182/bloodadvances.2023010027 . PubMed DOI PMC

Closse C, Dachary-Prigent J, Boisseau MR. Phosphatidylserine-related adhesion of human erythrocytes to vascular endothelium. Br J Haematol. 1999;107(2):300–2. https://doi.org/10.1046/j.1365-2141.1999.01718.x . PubMed DOI

Setty BN, Kulkarni S, Stuart MJ. Role of erythrocyte phosphatidylserine in sickle red cell-endothelial adhesion. Blood. 2002;99(5):1564–71. https://doi.org/10.1182/blood.v99.5.1564 . PubMed DOI

Borst O, Abed M, Alesutan I, Towhid ST, Qadri SM, Föller M, et al. Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX. Am J Physiol Cell Physiol. 2012;302(4):C644–51. https://doi.org/10.1152/ajpcell.00340.2011 . PubMed DOI

Abed M, Towhid ST, Feger M, Schmidt S, Kuro OM, Gawaz M, et al. Adhesion of klotho-deficient eryptotic erythrocytes to endothelial cells. Acta Physiol (Oxf). 2013;207(3):485–93. https://doi.org/10.1111/apha.12046 . PubMed DOI

Nicolay JP, Thorn V, Daniel C, Amann K, Siraskar B, Lang F, et al. Cellular stress induces erythrocyte assembly on intravascular von Willebrand factor strings and promotes microangiopathy. Sci Rep. 2018;8(1):10945. https://doi.org/10.1038/s41598-018-28961-2 . PubMed DOI PMC

Lang F, Gulbins E, Lang PA, Zappulla D, Föller M. Ceramide in suicidal death of erythrocytes. Cell Physiol Biochem. 2010;26(1):21–8. https://doi.org/10.1159/000315102 . PubMed DOI

Lang E, Bissinger R, Gulbins E, Lang F. Ceramide in the regulation of eryptosis, the suicidal erythrocyte death. Apoptosis. 2015;20(5):758–67. https://doi.org/10.1007/s10495-015-1094-4 . PubMed DOI

Lang KS, Myssina S, Brand V, Sandu C, Lang PA, Berchtold S, et al. Involvement of ceramide in hyperosmotic shock-induced death of erythrocytes. Cell Death Differ. 2004;11(2):231–43. https://doi.org/10.1038/sj.cdd.4401311 . PubMed DOI

Lang KS, Lang PA, Bauer C, Duranton C, Wieder T, Huber SM, et al. Mechanisms of suicidal erythrocyte death. Cell Physiol Biochem. 2005;15(5):195–202. https://doi.org/10.1159/000086406 . PubMed DOI

Lang PA, Kempe DS, Myssina S, Tanneur V, Birka C, Laufer S, et al. PGE2 in the regulation of programmed erythrocyte death. Cell Death Differ. 2005;12(5):415–28. https://doi.org/10.1038/sj.cdd.4401561 . PubMed DOI

Klarl BA, Lang PA, Kempe DS, Niemoeller OM, Akel A, Sobiesiak M, et al. Protein kinase C mediates erythrocyte “programmed cell death” following glucose depletion. Am J Physiol Cell Physiol. 2006;290(1):C244–53. https://doi.org/10.1152/ajpcell.00283.2005 . PubMed DOI

Tkachenko A, Onishchenko A. Casein kinase 1α mediates eryptosis: a review. Apoptosis. 2023;28(1–2):1–19. https://doi.org/10.1007/s10495-022-01776-3 . PubMed DOI

Zhang Y, Xu Y, Zhang S, Lu Z, Li Y, Zhao B. The regulation roles of Ca PubMed DOI

Mandal D, Moitra PK, Saha S, Basu J. Caspase 3 regulates phosphatidylserine externalization and phagocytosis of oxidatively stressed erythrocytes. FEBS Lett. 2002;513(2):184–8. https://doi.org/10.1016/S0014-5793(02)02294-9 . PubMed DOI

Ma N, Xu E, Luo Q, Song G. Rac1: a regulator of cell migration and a potential target for cancer therapy. Molecules. 2023;28(7):2976. PubMed DOI PMC

Paone S, D’Alessandro S, Parapini S, Celani F, Tirelli V, Pourshaban M, et al. Characterization of the erythrocyte GTPase Rac1 in relation to Plasmodium falciparum invasion. Sci Rep. 2020;10(1):22054. https://doi.org/10.1038/s41598-020-79052-0 . PubMed DOI PMC

Kalfa TA, Pushkaran S, Mohandas N, Hartwig JH, Fowler VM, Johnson JF, et al. Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood. 2006;108(12):3637–45. https://doi.org/10.1182/blood-2006-03-005942 . PubMed DOI PMC

Attanzio A, Frazzitta A, Cilla A, Livrea MA, Tesoriere L, Allegra M. 7-keto-cholesterol and cholestan-3beta, 5alpha, 6beta-triol induce eryptosis through distinct pathways leading to NADPH oxidase and nitric oxide synthase activation. Cell Physiol Biochem. 2019;53(6):933–47. https://doi.org/10.33594/000000186 . PubMed DOI

Alfhili MA, Alsughayyir J. Bufalin reprograms erythrocyte lifespan through p38 MAPK and Rac1 GTPase. Toxicon. 2024;240:107636. https://doi.org/10.1016/j.toxicon.2024.107636 . PubMed DOI

Alfhili MA, Alghareeb SA, Alotaibi GA, Alsughayyir J. Galangin triggers eryptosis and hemolysis through Ca2+ nucleation and metabolic collapse mediated by PKC/CK1α/COX/p38/Rac1 signaling axis. Int J Mol Sci. 2024;25(22):12267. PubMed DOI PMC

Alghareeb SA, Alsughayyir J, Alfhili MA. Stimulation of hemolysis and eryptosis by α-mangostin through Rac1 GTPase and oxidative injury in human red blood cells. Molecules. 2023;28(18):6495. PubMed DOI PMC

Gajecki D, Gawryś J, Szahidewicz-Krupska E, Doroszko A. Role of erythrocytes in nitric oxide metabolism and paracrine regulation of endothelial function. Antioxidants. 2022. https://doi.org/10.3390/antiox11050943 . PubMed DOI PMC

Cortese-Krott MM, Kelm M. Endothelial nitric oxide synthase in red blood cells: key to a new erythrocrine function? Redox Biol. 2014;2:251–8. https://doi.org/10.1016/j.redox.2013.12.027 . PubMed DOI PMC

Azarov I, Huang KT, Basu S, Gladwin MT, Hogg N, Kim-Shapiro DB. Nitric oxide scavenging by red blood cells as a function of hematocrit and oxygenation. J Biol Chem. 2005;280(47):39024–32. https://doi.org/10.1074/jbc.M509045200 . PubMed DOI

Helms CC, Gladwin MT, Kim-Shapiro DB. Erythrocytes and vascular function: oxygen and nitric oxide. Front Physiol. 2018. https://doi.org/10.3389/fphys.2018.00125 . PubMed DOI PMC

Nasoni MG, Crinelli R, Iuliano L, Luchetti F. When nitrosative stress hits the endoplasmic reticulum: possible implications in oxLDL/oxysterols-induced endothelial dysfunction. Free Radic Biol Med. 2023;208:178–85. https://doi.org/10.1016/j.freeradbiomed.2023.08.008 . PubMed DOI

Premont RT, Reynolds JD, Zhang R, Stamler JS. Red blood cell-mediated S-nitrosohemoglobin-dependent vasodilation: lessons learned from a β-globin Cys93 knock-in mouse. Antioxid Redox Signal. 2021;34(12):936–61. https://doi.org/10.1089/ars.2020.8153 . PubMed DOI PMC

Padmavathi P, Raghu PS, Reddy VD, Bulle S, Marthadu SB, Maturu P, et al. Chronic cigarette smoking-induced oxidative/nitrosative stress in human erythrocytes and platelets. Mol Cell Toxicol. 2018;14(1):27–34. https://doi.org/10.1007/s13273-018-0004-6 . DOI

Tkachenko M, Onishchenko A, Tryfonyuk L, Butov D, Kot K, Novikova V, et al. Human chemerin induces eryptosis at concentrations exceeding circulating levels. Biocell. 2024;48(8):1197–208. https://doi.org/10.32604/biocell.2024.050206 . DOI

Prokopiuk V, Onishchenko A, Pazura Y, Bespalova I, Kökbaş U, Tryfonyuk L, et al. Nanostructured zinc carbonate hydroxide microflakes: assessing the toxicity against erythrocytes and L929 cellsin vitro. Nanotechnology. 2024. https://doi.org/10.1088/1361-6528/ad9aac . PubMed DOI

Ghashghaeinia M, Bobbala D, Wieder T, Koka S, Brück J, Fehrenbacher B, et al. Targeting glutathione by dimethylfumarate protects against experimental malaria by enhancing erythrocyte cell membrane scrambling. Am J Physiol Cell Physiol. 2010;299(4):C791-804. https://doi.org/10.1152/ajpcell.00014.2010 . PubMed DOI

Lau IP, Chen H, Wang J, Ong HC, Leung KC, Ho HP, et al. In vitro effect of CTAB- and PEG-coated gold nanorods on the induction of eryptosis/erythroptosis in human erythrocytes. Nanotoxicology. 2012;6:847–56. https://doi.org/10.3109/17435390.2011.625132 . PubMed DOI

Jagadish S, Hemshekhar M, NaveenKumar SK, Sharath Kumar KS, Sundaram MS, Basappa, et al. Novel oxolane derivative DMTD mitigates high glucose-induced erythrocyte apoptosis by regulating oxidative stress. Toxicol Appl Pharmacol. 2017;334:167–79. https://doi.org/10.1016/j.taap.2017.09.008

Prokopiuk V, Onishchenko A, Tryfonyuk L, Posokhov Y, Gorbach T, Kot Y, et al. Marine polysaccharides carrageenans enhance eryptosis and alter lipid order of cell membranes in erythrocytes. Cell Biochem Biophys. 2024;82(2):747–66. https://doi.org/10.1007/s12013-024-01225-9 . PubMed DOI

Ghashghaeinia M, Giustarini D, Koralkova P, Köberle M, Alzoubi K, Bissinger R, et al. Pharmacological targeting of glucose-6-phosphate dehydrogenase in human erythrocytes by Bay 11–7082, parthenolide and dimethyl fumarate. Sci Rep. 2016;6:28754. https://doi.org/10.1038/srep28754 . PubMed DOI PMC

Rana RB, Jilani K, Shahid M, Riaz M, Ranjha MH, Bibi I, et al. Atorvastatin induced erythrocytes membrane blebbing. Dose Response. 2019;17(3):1559325819869076. https://doi.org/10.1177/1559325819869076 . PubMed DOI PMC

Naveed A, Jilani K, Siddique AB, Akbar M, Riaz M, Mushtaq Z, et al. Induction of erythrocyte shrinkage by omeprazole. Dose Response. 2020;18(3):1559325820946941. https://doi.org/10.1177/1559325820946941 . PubMed DOI PMC

Dreischer P, Duszenko M, Stein J, Wieder T. Eryptosis: programmed death of nucleus-free, iron-filled blood cells. Cells. 2022;11(3):503. PubMed DOI PMC

Mandal D, Mazumder A, Das P, Kundu M, Basu J. Fas-, caspase 8-, and caspase 3-dependent signaling regulates the activity of the aminophospholipid translocase and phosphatidylserine externalization in human erythrocytes*. J Biol Chem. 2005;280(47):39460–7. https://doi.org/10.1074/jbc.M506928200 . PubMed DOI

Restivo I, Attanzio A, Giardina IC, Di Gaudio F, Tesoriere L, Allegra M. Cigarette smoke extract induces p38 MAPK-initiated, fas-mediated eryptosis. Int J Mol Sci. 2022;23(23):14730. PubMed DOI PMC

Restivo I, Attanzio A, Tesoriere L, Allegra M, Garcia-Llatas G, Cilla A. A mixture of dietary plant sterols at nutritional relevant serum concentration inhibits extrinsic pathway of eryptosis induced by cigarette smoke extract. Int J Mol Sci. 2023. https://doi.org/10.3390/ijms24021264 . PubMed DOI PMC

Restivo I, Giardina IC, Barone R, Cilla A, Burgio S, Allegra M, et al. Indicaxanthin prevents eryptosis induced by cigarette smoke extract by interfering with active Fas-mediated signaling. Biofactors. 2024. https://doi.org/10.1002/biof.2051 . PubMed DOI

Romero PJ, Romero EA. The role of calcium metabolism in human red blood cell ageing: a proposal. Blood Cells Mol Dis. 1999;25(1):9–19. https://doi.org/10.1006/bcmd.1999.0222 . PubMed DOI

Bogdanova A, Makhro A, Wang J, Lipp P, Kaestner L. Calcium in red blood cells—a perilous balance. Int J Mol Sci. 2013;14(5):9848–72. PubMed DOI PMC

Romero PJ, Romero EA, Winkler MD. Ionic calcium content of light dense human red cells separated by Percoll density gradients. Biochim Biophys Acta. 1997;1323(1):23–8. https://doi.org/10.1016/s0005-2736(96)00141-1 . PubMed DOI

Lew VL, Tiffert T. On the mechanism of human red blood cell longevity: roles of calcium, the sodium pump, PIEZO1, and Gardos channels. Front Physiol. 2017. https://doi.org/10.3389/fphys.2017.00977 . PubMed DOI PMC

Wesseling MC, Wagner-Britz L, Huppert H, Hanf B, Hertz L, Nguyen DB, et al. Phosphatidylserine exposure in human red blood cells depending on cell age. Cell Physiol Biochem. 2016;38(4):1376–90. https://doi.org/10.1159/000443081 . PubMed DOI

Bernhardt I, Nguyen DB, Wesseling MC, Kaestner L. Intracellular Ca2+ concentration and phosphatidylserine exposure in healthy human erythrocytes in dependence on in vivo cell age. Front Physiol. 2020. https://doi.org/10.3389/fphys.2019.01629 . PubMed DOI PMC

Franco RS, Puchulu-Campanella ME, Barber LA, Palascak MB, Joiner CH, Low PS, et al. Changes in the properties of normal human red blood cells during in vivo aging. Am J Hematol. 2013;88(1):44–51. https://doi.org/10.1002/ajh.23344 . PubMed DOI

Khandelwal S, Saxena RK. A role of phosphatidylserine externalization in clearance of erythrocytes exposed to stress but not in eliminating aging populations of erythrocyte in mice. Exp Gerontol. 2008;43(8):764–70. https://doi.org/10.1016/j.exger.2008.05.002 . PubMed DOI

Boas FE, Forman L, Beutler E. Phosphatidylserine exposure and red cell viability in red cell aging and in hemolytic anemia. Proc Natl Acad Sci U S A. 1998;95(6):3077–81. https://doi.org/10.1073/pnas.95.6.3077 . PubMed DOI PMC

Dinkla S, Peppelman M, Van Der Raadt J, Atsma F, Novotný VM, Van Kraaij MG, et al. Phosphatidylserine exposure on stored red blood cells as a parameter for donor-dependent variation in product quality. Blood Transfus. 2014;12(2):204–9. https://doi.org/10.2450/2013.0106-13 . PubMed DOI PMC

Connor J, Pak CC, Schroit AJ. Exposure of phosphatidylserine in the outer leaflet of human red blood cells. Relationship to cell density, cell age, and clearance by mononuclear cells. J Biol Chem. 1994;269(4):2399–404. PubMed DOI

Koshkaryev A, Yedgar S, Relevy H, Fibach E, Barshtein G. Acridine orange induces translocation of phosphatidylserine to red blood cell surface. Am J Physiol Cell Physiol. 2003;285(3):720–2. https://doi.org/10.1152/ajpcell.00542.2002 . DOI

DeJong K, Bhagat A, Emerson RK, Kuypers FA. Flippase activity decreases throughout erythrocyte life-span in normal and sickle mice. Blood. 2006;108(11):3786. https://doi.org/10.1182/blood.V108.11.3786.3786 . DOI

Rosales C, Uribe-Querol E. Phagocytosis: a fundamental process in immunity. Biomed Res Int. 2017;2017:9042851. https://doi.org/10.1155/2017/9042851 . PubMed DOI PMC

Pulica R, Aquib A, Varsanyi C, Gadiyar V, Wang Z, Frederick T, et al. Dys-regulated phosphatidylserine externalization as a cell intrinsic immune escape mechanism in cancer. Cell Commun Signal. 2025;23(1):131. https://doi.org/10.1186/s12964-025-02090-6 . PubMed DOI PMC

Yoshida H, Kawane K, Koike M, Mori Y, Uchiyama Y, Nagata S. Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells. Nature. 2005;437(7059):754–8. https://doi.org/10.1038/nature03964 . PubMed DOI

Akel A, Wagner CA, Kovacikova J, Kasinathan RS, Kiedaisch V, Koka S, et al. Enhanced suicidal death of erythrocytes from gene-targeted mice lacking the Cl-/HCO(3)(-) exchanger AE1. Am J Physiol Cell Physiol. 2007;292(5):C1759–67. https://doi.org/10.1152/ajpcell.00158.2006 . PubMed DOI

Wieder T, Lang F. Erythrozyten. In: Pötzsch B, Madlener K, editors. Hämostaseologie. Berlin, Heidelberg: Springer Berlin Heidelberg; 2010. p. 113–9. https://doi.org/10.1007/978-3-642-01544-1_14 .

Lang PA, Kasinathan RS, Brand VB, Duranton C, Lang C, Koka S, et al. Accelerated clearance of Plasmodium-infected erythrocytes in sickle cell trait and annexin-A7 deficiency. Cell Physiol Biochem. 2009;24(5–6):415–28. https://doi.org/10.1159/000257529 . PubMed DOI

Ghashghaeinia M, Cluitmans JC, Akel A, Dreischer P, Toulany M, Köberle M, et al. The impact of erythrocyte age on eryptosis. Br J Haematol. 2012;157(5):606–14. https://doi.org/10.1111/j.1365-2141.2012.09100.x . PubMed DOI

de Back DZ, Kostova EB, van Kraaij M, van den Berg TK, van Bruggen R. Of macrophages and red blood cells; a complex love story. Front Physiol. 2014;5:9. https://doi.org/10.3389/fphys.2014.00009 . PubMed DOI PMC

Freitas Leal J, Vermeer H, Lazari D, van Garsse L, Brock R, Adjobo-Hermans M, et al. The impact of circulation in a heart-lung machine on function and survival characteristics of red blood cells. Artif Organs. 2020;44(8):892–9. https://doi.org/10.1111/aor.13682 . PubMed DOI PMC

Larsen FL, Katz S, Roufogalis BD, Brooks DE. Physiological shear stresses enhance the Ca2+ permeability of human erythrocytes. Nature. 1981;294(5842):667–8. https://doi.org/10.1038/294667a0 . PubMed DOI

Kuck L, Peart JN, Simmonds MJ. Calcium dynamically alters erythrocyte mechanical response to shear. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2020;1867(11):118802. https://doi.org/10.1016/j.bbamcr.2020.118802 . PubMed DOI

Kuck L, Peart JN, Simmonds MJ. Piezo1 regulates shear-dependent nitric oxide production in human erythrocytes. Am J Physiol Heart Circ Physiol. 2022;323(1):H24-h37. https://doi.org/10.1152/ajpheart.00185.2022 . PubMed DOI

Sangha GS, Weber CM, Sapp RM, Setua S, Thangaraju K, Pettebone M, et al. Mechanical stimuli such as shear stress and piezo1 stimulation generate red blood cell extracellular vesicles. Front Physiol. 2023. https://doi.org/10.3389/fphys.2023.1246910 . PubMed DOI PMC

Kuck L, McNamee AP, Bordukova M, Sadafi A, Marr C, Peart JN, et al. Lysis of human erythrocytes due to Piezo1-dependent cytosolic calcium overload as a mechanism of circulatory removal. Proc Natl Acad Sci U S A. 2024;121(36):e2407765121. https://doi.org/10.1073/pnas.2407765121 . PubMed DOI PMC

Tkachenko A, Alfhili MA, Alsughayyir J, Attanzio A, Al Mamun Bhuyan A, Bukowska B, et al. Current understanding of eryptosis: mechanisms, physiological functions, role in disease, pharmacological applications, and nomenclature recommendations. Cell Death Dis. 2025;16(1):467. https://doi.org/10.1038/s41419-025-07784-w . PubMed DOI PMC

Föller M, Sopjani M, Koka S, Gu S, Mahmud H, Wang K, et al. Regulation of erythrocyte survival by AMP-activated protein kinase. FASEB J. 2009;23(4):1072–80. https://doi.org/10.1096/fj.08-121772 . PubMed DOI

Virzì GM, Mattiotti M, Clementi A, Milan Manani S, Battaglia GG, Ronco C, et al. In vitro induction of eryptosis by uremic toxins and inflammation mediators in healthy red blood cells. J Clin Med. 2022. https://doi.org/10.3390/jcm11185329 . PubMed DOI PMC

Bester J, Pretorius E. Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity. Sci Rep. 2016;6:32188. https://doi.org/10.1038/srep32188 . PubMed DOI PMC

Rivera A, Jarolim P, Brugnara C. Modulation of Gardos channel activity by cytokines in sickle erythrocytes. Blood. 2002;99(1):357–603. https://doi.org/10.1182/blood.v99.1.357 . PubMed DOI

Durpès MC, Nebor D, du Mesnil PC, Mougenel D, Decastel M, Elion J, et al. Effect of interleukin-8 and RANTES on the Gardos channel activity in sickle human red blood cells: role of the Duffy antigen receptor for chemokines. Blood Cells Mol Dis. 2010;44(4):219–23. https://doi.org/10.1016/j.bcmd.2010.02.001 . PubMed DOI

Soma P, Bester J. Pathophysiological changes in erythrocytes contributing to complications of inflammation and coagulation in COVID-19. Front Physiol. 2022;13:899629. https://doi.org/10.3389/fphys.2022.899629 . PubMed DOI PMC

Weisel JW, Litvinov RI. Red blood cells: the forgotten player in hemostasis and thrombosis. J Thromb Haemost. 2019;17(2):271–82. https://doi.org/10.1111/jth.14360 . PubMed DOI PMC

Mahdi A, Wodaje T, Kövamees O, Tengbom J, Zhao A, Jiao T, et al. The red blood cell as a mediator of endothelial dysfunction in patients with familial hypercholesterolemia and dyslipidemia. J Intern Med. 2023;293(2):228–45. https://doi.org/10.1111/joim.13580 . PubMed DOI

Mahdi A, Collado A, Tengbom J, Jiao T, Wodaje T, Johansson N, et al. Erythrocytes induce vascular dysfunction in COVID-19. JACC: Basic to Translational Science. 2022;7(3, Part 1):193–204. https://doi.org/10.1016/j.jacbts.2021.12.003 . PubMed DOI PMC

Costantino S, Mohammed SA, Paneni F. Endothelial dysfunction in patients with type 2 diabetes: the truth is in the blood. J Clin Invest. 2025. https://doi.org/10.1172/jci193128 . PubMed DOI PMC

Li Z, Yan M, Wang Z, An Y, Wei X, Li T, et al. Ferroptosis of endothelial cells triggered by erythrophagocytosis contributes to thrombogenesis in uremia. Thromb Haemost. 2023;123(12):1116–28. https://doi.org/10.1055/a-2117-7890 . PubMed DOI PMC

Liu W, Östberg N, Yalcinkaya M, Dou H, Endo-Umeda K, Tang Y, et al. Erythroid lineage Jak2V617F expression promotes atherosclerosis through erythrophagocytosis and macrophage ferroptosis. J Clin Invest. 2022. https://doi.org/10.1172/jci155724 . PubMed DOI PMC

Puylaert P, Roth L, Van Praet M, Pintelon I, Dumitrascu C, van Nuijs A, et al. Effect of erythrophagocytosis-induced ferroptosis during angiogenesis in atherosclerotic plaques. Angiogenesis. 2023;26(4):505–22. https://doi.org/10.1007/s10456-023-09877-6 . PubMed DOI PMC

Whelihan MF, Zachary V, Orfeo T, Mann KG. Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation. Blood. 2012;120(18):3837–45. https://doi.org/10.1182/blood-2012-05-427856 . PubMed DOI PMC

Delbosc S, Bayles RG, Laschet J, Ollivier V, Ho-Tin-Noé B, Touat Z, et al. Erythrocyte efferocytosis by the arterial wall promotes oxidation in early-stage atheroma in humans. Front Cardiovasc Med. 2017;4:43. https://doi.org/10.3389/fcvm.2017.00043 . PubMed DOI PMC

Tkachenko A. Is eryptosis druggable? Ann Hematol. 2024. https://doi.org/10.1007/s00277-024-05713-z . PubMed DOI

Li Z, Zhang Z, Ren Y, Wang Y, Fang J, Yue H, et al. <article-title update="added">Aging and age‐related diseases: from mechanisms to therapeutic strategies. Biogerontology. 2021;22(2):165–87. https://doi.org/10.1007/s10522-021-09910-5 . PubMed DOI PMC

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–78. https://doi.org/10.1016/j.cell.2022.11.001 . PubMed DOI

Yadav S, Deepika, Maurya PK. A systematic review of red blood cells biomarkers in human aging. J Gerontol A Biol Sci Med Sci. 2024;79(4):glae004.  https://doi.org/10.1093/gerona/glae004

Kyriacou RP, Shibeeb S. Red blood cells and human aging: exploring their biomarker potential. Diagnostics. 2025;15(16):1993. PubMed DOI PMC

Wang F, Liu YH, Zhang T, Gao J, Xu Y, Xie GY, et al. Aging-associated changes in CD47 arrangement and interaction with thrombospondin-1 on red blood cells visualized by super-resolution imaging. Aging Cell. 2020;19(10):e13224. https://doi.org/10.1111/acel.13224 . PubMed DOI PMC

Schwarz-Ben Meir N, Glaser T, Kosower NS. Band 3 protein degradation by calpain is enhanced in erythrocytes of old people. Biochem J. 1991;275(Pt 1):47–52. https://doi.org/10.1042/bj2750047 . PubMed DOI PMC

Berliner N. Anemia in the elderly. Trans Am Clin Climatol Assoc. 2013;124:230–7. PubMed PMC

Gadó K, Khodier M, Virág A, Domján G, Dörnyei G. Anemia of geriatric patients. Physiol Int. 2022;109(2):119–34. https://doi.org/10.1556/2060.2022.00218 . PubMed DOI

Mohammadi A, Kazeminia M, Chogan A, Jalali A. Prevalence of anemia in older adults: a systematic and meta-analysis study. Int J Africa Nurs Sci. 2024;20:100739. https://doi.org/10.1016/j.ijans.2024.100739 . DOI

Lupescu A, Bissinger R, Goebel T, Salker MS, Alzoubi K, Liu G, et al. Enhanced suicidal erythrocyte death contributing to anemia in the elderly. Cell Physiol Biochem. 2015;36(2):773–83. https://doi.org/10.1159/000430137 . PubMed DOI

Guo J, Huang X, Dou L, Yan M, Shen T, Tang W, et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther. 2022;7(1):391. https://doi.org/10.1038/s41392-022-01251-0 . PubMed DOI PMC

Stevenson A, Lopez D, Khoo P, Kalaria RN, Mukaetova-Ladinska EB. Exploring erythrocytes as blood biomarkers for Alzheimer’s disease. J Alzheimers Dis. 2017;60(3):845–57. https://doi.org/10.3233/jad-170363 . PubMed DOI

Sitnikova V, Nurkhametova D, Braidotti N, Ciubotaru CD, Giudice L, Impola U, et al. Increased activity of Piezo1 channel in red blood cells is associated with Alzheimer’s disease-related dementia. Alzheimers Dement. 2025;21(6):e70368. https://doi.org/10.1002/alz.70368 . PubMed DOI PMC

Pretorius E, Swanepoel AC, Buys AV, Vermeulen N, Duim W, Kell DB. Eryptosis as a marker of Parkinson’s disease. Aging (Albany NY). 2014;6(10):788–819. https://doi.org/10.18632/aging.100695 . PubMed DOI

Wang YC, Huang AP, Yuan SP, Huang CY, Wu CC, Poly TN, et al. Association between anemia and risk of Parkinson disease. Behav Neurol. 2021;2021:8360627. https://doi.org/10.1155/2021/8360627 . PubMed DOI PMC

Yang Y, Nie X, Wang Y, Sun J, Gao X, Zhang J. Evolving insights into erythrocytes in synucleinopathies. Trends Neurosci. 2024;47(9):693–707. https://doi.org/10.1016/j.tins.2024.06.005 . PubMed DOI

Abraham S, Soundararajan CC, Vivekanandhan S, Behari M. Erythrocyte antioxidant enzymes in Parkinson’s disease. Indian J Med Res. 2005;121(2):111–5. PubMed

Denis HL, de Rus Jacquet A, Alpaugh M, Panisset M, Barker RA, Boilard É, et al. Erythrocyte-derived extracellular vesicles transcytose across the blood-brain barrier to induce Parkinson’s disease-like neurodegeneration. Fluids Barriers CNS. 2025;22(1):38. https://doi.org/10.1186/s12987-025-00646-9 . PubMed DOI PMC

Attanasio P, Bissinger R, Haverkamp W, Pieske B, Wutzler A, Lang F. Enhanced suicidal erythrocyte death in acute cardiac failure. Eur J Clin Invest. 2015;45(12):1316–24. https://doi.org/10.1111/eci.12555 . PubMed DOI

Mahmud H, Ruifrok WP, Westenbrink BD, Cannon MV, Vreeswijk-Baudoin I, van Gilst WH, et al. Suicidal erythrocyte death, eryptosis, as a novel mechanism in heart failure-associated anaemia. Cardiovasc Res. 2013;98(1):37–46. https://doi.org/10.1093/cvr/cvt010 . PubMed DOI

Pinzón-Díaz CE, Calderón-Salinas JV, Rosas-Flores MM, Hernández G, López-Betancourt A, Quintanar-Escorza MA. Eryptosis and oxidative damage in hypertensive and dyslipidemic patients. Mol Cell Biochem. 2018;440(1–2):105–13. https://doi.org/10.1007/s11010-017-3159-x . PubMed DOI

Calderón-Salinas JV, Muñoz-Reyes EG, Guerrero-Romero JF, Rodríguez-Morán M, Bracho-Riquelme RL, Carrera-Gracia MA, et al. Eryptosis and oxidative damage in type 2 diabetic mellitus patients with chronic kidney disease. Mol Cell Biochem. 2011;357(1–2):171–9. https://doi.org/10.1007/s11010-011-0887-1 . PubMed DOI

An X, Yu W, Liu J, Tang D, Yang L, Chen X. Oxidative cell death in cancer: mechanisms and therapeutic opportunities. Cell Death Dis. 2024;15(8):556. https://doi.org/10.1038/s41419-024-06939-5 . PubMed DOI PMC

Obeagu EI, Igwe MC, Obeagu GU. Oxidative stress’s impact on red blood cells: unveiling implications for health and disease. Medicine (Baltimore). 2024;103(9):e37360. https://doi.org/10.1097/md.0000000000037360 . PubMed DOI

Lang E, Bissinger R, Qadri SM, Lang F. Suicidal death of erythrocytes in cancer and its chemotherapy: a potential target in the treatment of tumor-associated anemia. Int J Cancer. 2017;141(8):1522–8. https://doi.org/10.1002/ijc.30800 . PubMed DOI

Bissinger R, Schumacher C, Qadri SM, Honisch S, Malik A, Götz F, et al. Enhanced eryptosis contributes to anemia in lung cancer patients. Oncotarget. 2016;7(12):14002–14. https://doi.org/10.18632/oncotarget.7286 . PubMed DOI PMC

Biasini GM, Botrè F, de la Torre X, Donati F. Age-markers on the red blood cell surface and erythrocyte microparticles may constitute a multi-parametric strategy for detection of autologous blood transfusion. Sports Med Open. 2023;9(1):113. https://doi.org/10.1186/s40798-023-00662-9 . PubMed DOI PMC

Yoshida T, Prudent M, D’Alessandro A. Red blood cell storage lesion: causes and potential clinical consequences. Blood Transfus. 2019;17(1):27–52. https://doi.org/10.2450/2019.0217-18 . PubMed DOI PMC

Tran LNT, González-Fernández C, Gomez-Pastora J. Impact of different red blood cell storage solutions and conditions on cell function and viability: a systematic review. Biomolecules. 2024;14(7):813. PubMed DOI PMC

Lang E, Pozdeev VI, Xu HC, Shinde PV, Behnke K, Hamdam JM, et al. Storage of erythrocytes induces suicidal erythrocyte death. Cell Physiol Biochem. 2016;39(2):668–76. https://doi.org/10.1159/000445657 . PubMed DOI

Hamsanathan S, Gurkar AU. Lipids as regulators of cellular senescence. Front Physiol. 2022. https://doi.org/10.3389/fphys.2022.796850 . PubMed DOI PMC

Kurmangaliyeva S, Baktikulova K, Tkachenko A, Seitkhanova B, Tryfonyuk L, Rakhimzhanova F, et al. Eryptosis in liver diseases: contribution to anemia and hypercoagulation. Med Sci (Basel). 2025;13(3):125. PubMed

Bartosz G. Erythrocyte aging: physical and chemical membrane changes. Gerontology. 1991;37(1–3):33–67. https://doi.org/10.1159/000213251 . PubMed DOI

Tkachenko A. Hemocompatibility studies in nanotoxicology: hemolysis or eryptosis? (a review). Toxicol In Vitro. 2024;98:105814. https://doi.org/10.1016/j.tiv.2024.105814 . PubMed DOI

Kiefer CR, Snyder LM. Oxidation and erythrocyte senescence. Curr Opin Hematol. 2000;7(2):113–6. https://doi.org/10.1097/00062752-200003000-00007 . PubMed DOI

Seki M, Arashiki N, Takakuwa Y, Nitta K, Nakamura F. Reduction in flippase activity contributes to surface presentation of phosphatidylserine in human senescent erythrocytes. J Cell Mol Med. 2020;24(23):13991–4000. https://doi.org/10.1111/jcmm.16010 . PubMed DOI PMC

Kuypers FA, de Jong K. The role of phosphatidylserine in recognition and removal of erythrocytes. Cell Mol Biol (Noisy-le-grand). 2004;50(2):147–58. PubMed

Lee S-J, Park S-Y, Jung M-Y, Bae SM, Kim I-S. Mechanism for phosphatidylserine-dependent erythrophagocytosis in mouse liver. Blood. 2011;117(19):5215–23. https://doi.org/10.1182/blood-2010-10-313239 . PubMed DOI

Seki M, Arashiki N, Hanafusa N, Hoshino J, Tsuchiya K, Nakamura F. #3627 phosphatidylserine exposure and shortened life span of erythrocytes in renal anemia. Nephrol Dial Transplant. 2023. https://doi.org/10.1093/ndt/gfad063c_3627 . DOI

Arashiki N, Takakuwa Y. Maintenance and regulation of asymmetric phospholipid distribution in human erythrocyte membranes: implications for erythrocyte functions. Curr Opin Hematol. 2017;24(3):167–72. https://doi.org/10.1097/moh.0000000000000326 . PubMed DOI

Kosower NS. Altered properties of erythrocytes in the aged. Am J Hematol. 1993;42(3):241–7. https://doi.org/10.1002/ajh.2830420302 . PubMed DOI

Martien S, Pluquet O, Vercamer C, Malaquin N, Martin N, Gosselin K, et al. Cellular senescence involves an intracrine prostaglandin E2 pathway in human fibroblasts. Biochim Biophys Acta. 2013;1831(7):1217–27. https://doi.org/10.1016/j.bbalip.2013.04.005 . PubMed DOI

Srour E, Martin N, Drullion C, De Schutter C, Giroud J, Pioger A, et al. Prostaglandin E(2) regulates senescence and post-senescence neoplastic escape in primary human keratinocytes. Aging (Albany NY). 2024;16(21):13201–24. https://doi.org/10.18632/aging.206149 . PubMed DOI