Avoid common mistakes on your manuscript.
Regulated cell death (RCD) modalities such as necroptosis, pyroptosis, ferroptosis, or cuproptosis have been extensively studied as a target for cancer therapy due to their ability to ensure cell death in apoptosis-resistant tumors or to modulate tumor microenvironment through emitting multiple immunogenic signals by dying cells [1, 2]. Recent progress in the field of RCD has contributed to unraveling the landscape of cell death processes in particular cell types. For instance, there is accumulating evidence that erythrocytes display a limited set of RCD pathways undergoing senescence, eryptosis, and necroptosis [3,4,5,6]. A recent review has demonstrated that eryptosis of mature erythrocytes differs from apoptosis of nucleated cells at the level of crucial signaling pathways [7]. This is a prerequisite condition for developing eryptosis-specific pharmaceutical modulators. Overall, eryptosis is a controlled RCD of mature erythrocytes associated with cell shrinkage, membrane blebbing and phospholipid scrambling mediated primarily by intracellular Ca2+ elevation, reactive oxygen species (ROS) and ceramide accumulation [3, 6]. Clinically, accelerated eryptosis may result in anemia. Eryptosis-associated anemia has been reported in elderly individuals, acute cardiac failure, end stage renal disease, hypertension, metabolic syndrome, diabetes mellitus type 2, systemic lupus erythematosus, arteritis, lung cancer, etc. Thus, therapeutic interventions aiming to reduce eryptosis might be beneficial.
Which signaling pathway in eryptosis is druggable? Notably, phosphatidylserine (PS) externalization is a crucial event that defines eryptosis. Despite the importance of intracellular Ca2+ elevation, oxidative stress, or ceramide signaling, occasional activation of eryptosis-regulating kinases (p38 MAPK, casein kinase 1α, protein kinase C, etc.), caspase-3 and calpain, these events are not essential for eryptosis to occur [6, 7]. At the same time, phospholipid scrambling is observed in senescent or stressed erythrocytes [5]. Moreover, although PS translocation has not yet been shown in necroptosis of erythrocytes, it is evident that it is observed in necroptosis of nucleated cells [8]. Thus, it seems logical that pharmaceutical reduction of PS externalization prevents clearance of not only eryptotic, but also senescent, compromised and probably necroptotic erythrocytes that display PS on their surface. Thus, it can be assumed that our current understanding of eryptosis signaling makes it challenging to selectively inhibit this pathway without affecting other PS-exposing red blood cells. On the other hand, eryptosis induction has been suggested as a strategy for treating malaria [9]. The effectiveness of this approach is still debatable due to the complex and often conflicting role of eryptosis in malaria pathogenesis. Moreover, multiple generally accepted eryptosis-inducing agents have failed to trigger eryptosis in P.falciparum-infected erythrocytes [9].
Thus, although therapeutic interventions modulating eryptosis (both inhibition and induction) seem to be promising in multiple diseases, our knowledge of eryptotic machinery and signaling is limited to fully exploit options of eryptosis targeting.
Data availability
No datasets were generated or analysed during the current study.
References
Kroemer G, Galassi C, Zitvogel L, Galluzzi L (2022) Immunogenic cell stress and death. Nat Immunol 23(4):487–500. https://doi.org/10.1038/s41590-022-01132-2
Tong X, Tang R, Xiao M, Xu J, Wang W, Zhang B, Liu J, Yu X, Shi S (2022) Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J Hematol Oncol 15(1):174. https://doi.org/10.1186/s13045-022-01392-3
Lang F, Qadri SM (2012) Mechanisms and significance of eryptosis, the suicidal death of erythrocytes. Blood Purif 33(1–3):125–130. https://doi.org/10.1159/000334163
LaRocca TJ, Stivison EA, Hod EA, Spitalnik SL, Cowan PJ, Randis TM, Ratner AJ (2014) Human-specific bacterial pore-forming toxins induce programmed necrosis in erythrocytes. mBio 5(5):e01251–e01214. https://doi.org/10.1128/mBio.01251-14
Thiagarajan P, Parker CJ, Prchal JT (2021) How do Red Blood cells die? Frontiers in physiology 12. https://doi.org/10.3389/fphys.2021.655393
Tkachenko A, Onishchenko A (2023) Casein kinase 1α mediates eryptosis: a review. Apoptosis 28(1–2):1–19. https://doi.org/10.1007/s10495-022-01776-3
Tkachenko A (2023) Apoptosis and eryptosis: similarities and differences. Apoptosis. https://doi.org/10.1007/s10495-023-01915-4
Shlomovitz I, Speir M, Gerlic M (2019) Flipping the dogma - phosphatidylserine in non-apoptotic cell death. Cell Commun Signal 17(1):139. https://doi.org/10.1186/s12964-019-0437-0
Boulet C, Gaynor TL, Carvalho TG (2021) Eryptosis and Malaria: New Experimental guidelines and Re-evaluation of the antimalarial potential of eryptosis inducers. Front Cell Infect Microbiol 11:630812. https://doi.org/10.3389/fcimb.2021.630812
Funding
The study was not funded in any way.
Author information
Authors and Affiliations
Contributions
The author confirms sole responsibility for the manuscript preparation.
Corresponding author
Ethics declarations
Ethical approval
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Tkachenko, A. Is eryptosis druggable?. Ann Hematol 103, 1791–1792 (2024). https://doi.org/10.1007/s00277-024-05713-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-024-05713-z