Fol. Biol. 2025, 71, 180-191
https://doi.org/10.14712/fb2025.0004
Nerol Activates Ca2+-Dependent Oxidative Eryptosis and Haemolysis-like Cell Death via Caspase/PKC/RIP1/p38 MAPK/CK1α, Energy Depletion and Ceramide Accumulation
Mohrah A. Alalshaikh
, Jawaher Alsughayyir, Sabiha Fatima, Mohammad A. Alfhili
, Jawaher Alsughayyir, Sabiha Fatima, Mohammad A. Alfhili
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
Received July 26, 2025
Accepted September 15, 2025
References
1. , M. A., Alghareeb, S. A., Alotaibi, G. A. et al. (2024) Galangin triggers eryptosis and hemolysis through Ca2+ nucleation and metabolic collapse mediated by PKC/CK1α/COX/p38/Rac1 signaling axis. Int. J. Mol. Med. 25, 12267.
2. Alfhili, M. A., Lee, M. H. (2021) Flow cytofluorometric analysis of molecular mechanisms of premature red blood cell death. In: Toxicology and Environmental Toxicogenomics Principles, Methods, and Application, eds. Pan, X., Zhang, B., pp. 155-165, Humana, Springer, New York.
3. , A., Frazzitta, A., Cilla, A. et al. (2019) 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. 53, 933-947.
4. , G., Cox, G. (2022) Light and scanning electron microscopy of red blood cells from humans and animal species providing insights into molecular cell biology. Front. Physiol. 13, 838071.
<https://doi.org/10.3389/fphys.2022.838071>
5. , M. L., Islam, M. T., Laylson da Silva Oliveira, G. et al. (2022) Cytotoxic and antioxidant properties of natural bioactive monoterpenes nerol, estragole, and 3,7-dimethyl-1-octanol. Adv. Pharmacol. Pharm. Sci. 2022, 8002766.
6. , P., Duszenko, M., Stein, J. et al. (2022) Eryptosis: programmed death of nucleus-free, iron-filled blood cells. Cells 11, 1-13.
<https://doi.org/10.3390/cells11030503>
7. , M. and Lang, F. (2020) Ion transport in eryptosis, the suicidal death of erythrocytes. Front. Cell Dev. Biol. 8, 1-9.
<https://doi.org/10.3389/fcell.2020.00597>
8. , M. El, Hafner, S., Lang, S. J. et al. (2019) A novel polyhalogenated monoterpene induces cell cycle arrest and apoptosis in breast cancer cells. Mar. Drugs 17, 437.
<https://doi.org/10.3390/md17080437>
9. , S., Zelenak, C., Fajol, A. et al. (2011) P38 MAPK activation and function following osmotic shock of erythrocytes. Cell. Physiol. Biochem. 28, 1279-1286.
<https://doi.org/10.1159/000335859>
10. , A., Pushkaran, S., Konstantinidis, D. G. et al. (2013) Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood 121, 2099-2107.
<https://doi.org/10.1182/blood-2012-07-441188>
11. , M., Koralkova, P., Giustarini, D. et al. (2020) The specific PKC-α inhibitor chelerythrine blunts costunolide-induced eryptosis. Apoptosis 25, 674-685.
<https://doi.org/10.1007/s10495-020-01620-6>
12. , M.-L., Li, X.-Y., Guo, Y.-Q. et al. (2025) Nerol attenuates doxorubicin-induced heart failure by inhibiting cardiomyocyte apoptosis in rats. Eur. J. Pharmacol. 987, 177203.
<https://doi.org/10.1016/j.ejphar.2024.177203>
13. , R., Ray, P., Sarkar, C. et al. (2022) Natural compounds or their derivatives against breast cancer: a computational study. Biomed. Res. Int. 2022, 5886269.
<https://doi.org/10.1155/2022/5886269>
14. , S., Jilani, K., Sikandar, M. et al. (2020) Stimulation of erythrocyte membrane blebbing by naproxen sodium. Dose Response 18, 1559325819899259.
<https://doi.org/10.1177/1559325819899259>
15. , J., Lang, E., Bissinger, R. et al. (2014) Stimulation of erythrocyte cell membrane scrambling by mitotane. Cell. Physiol. Biochem. 33, 1516-1526.
<https://doi.org/10.1159/000358715>
16. , P., Normant, E., Miskin, H. et al. (2020) Targeting casein kinase 1 (Ck1) in hematological cancers. Int. J. Mol. Sci. 21, 1-19.
<https://doi.org/10.3390/ijms21239026>
17. , S., Zhang, M., Sun, J. et al. (2018) Casein kinase 1α: biological mechanisms and theranostic potential. Cell Commun. Signal. 16, 23.
<https://doi.org/10.1186/s12964-018-0236-z>
18. , E., Park, K. A., Shen, H.-M. et al. (2022) The resurrection of RIP kinase 1 as an early cell death checkpoint regulator - a potential target for therapy in the necroptosis era. Exp. Mol. Med. 54, 1401-1411.
<https://doi.org/10.1038/s12276-022-00847-4>
19. , C. A., Pérez de la Lastra, J. M., Plou, F. J. et al. (2021) The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. Int. J. Mol. Sci. 22, 4642.
<https://doi.org/10.3390/ijms22094642>
20. , M. V., Repko, B. M., Krasik, E. F. et al. (2003) Polyethylene glycol additives reduce hemolysis in red blood cell suspensions exposed to mechanical stress. ASAIO J. 49, 537-542.
<https://doi.org/10.1097/01.MAT.0000084176.30221.CF>
21. , H. E., Ibrahim, H.-I. M., Darrag, H. M. et al. (2021) Insight into analysis of essential oil from anisosciadium ianatum boiss. – chemical composition, molecular docking, and mitigation of Hepg2 cancer cells through apoptotic markers. Plants (Basel) 11, 66.
22. , B. A., Lang, P. A., Kempe, D. S. et al. (2006) Protein kinase C mediates erythrocyte “programmed cell death” following glucose depletion. Am. J. Physiol. Cell Physiol. 290, C244-C253.
<https://doi.org/10.1152/ajpcell.00283.2005>
23. , E., Bissinger, R., Gulbins, E. et al. (2015) Ceramide in the regulation of eryptosis, the suicidal erythrocyte death. Apoptosis 20, 758-767.
<https://doi.org/10.1007/s10495-015-1094-4>
24. , E., Bissinger, R., Qadri, S. M. et al. (2017) Suicidal death of erythrocytes in cancer and its chemotherapy: a potential target in the treatment of tumor-associated anemia. Int. J. Cancer 141, 1522-1528.
<https://doi.org/10.1002/ijc.30800>
25. , E., Lang, F. (2015) Mechanisms and pathophysiological significance of eryptosis, the suicidal erythrocyte death. Semin. Cell Dev. Biol. 39, 35-42.
<https://doi.org/10.1016/j.semcdb.2015.01.009>
26. , K. S., Myssina, S., Lang, P. A. et al. (2004) Inhibition of erythrocyte phosphatidylserine exposure by urea and Cl−. Am. J. Physiol. Ren. Physiol. 286, 1046-1053.
<https://doi.org/10.1152/ajprenal.00263.2003>
27. , T. J., Sosunov, S. A., Shakerley, N. L. et al. (2016) Hyperglycemic conditions prime cells for RIP1-dependent necroptosis. J. Biol. Chem. 291, 13753-13761.
<https://doi.org/10.1074/jbc.M116.716027>
28. , T. Q., Da Fonseca, A. C. C., Duarte, A. B. S. et al. (2022) A narrative review of the antitumor activity of monoterpenes from essential oils: an update. Biomed Res. Int. 2022, 6317201.
<https://doi.org/10.1155/2022/6317201>
29. , A., Bissinger, R., Jilani, K. et al. (2015) Stimulation of erythrocyte cell membrane scrambling by nystatin. Basic Clin. Pharmacol. Toxicol. 116, 47-52.
<https://doi.org/10.1111/bcpt.12279>
30. Bhuyan, A. Al, Bissinger, R., Cao, H. et al. (2017) Triggering of suicidal erythrocyte death by exemestane. Cell. Physiol. Biochem. 42, 1-12.
31. , S., Carrino, M., Piazza, F. (2017) Role of protein kinases CK1α and CK2 in multiple myeloma: regulation of pivotal survival and stress-managing pathways. J. Hematol. Oncol. 10, 157.
<https://doi.org/10.1186/s13045-017-0529-5>
32. , C., Peng, F., Yin, W. et al. (2022) Increased suicidal erythrocyte death in patients with hepatitis B-related acute-on-chronic liver failure. Am. J. Physiol. Gastrointest. Liver Physiol. 323, G9-G20.
<https://doi.org/10.1152/ajpgi.00050.2020>
33. , M., Choudhary, S., Khan, M. A. et al. (2021) Lemongrass essential oil components with antimicrobial and anticancer activities. Antioxidants (Basel) 11, 20.
<https://doi.org/10.3390/antiox11010020>
34. , M., Nithindran, G. S. S., Ranjithvishal, R. V. et al. (2023) Influence of uric acid on erythrocytes subjected to H2O2-induced oxidative stress. Appl. In Vitro Toxicol. 9, 37-43.
<https://doi.org/10.1089/aivt.2023.0001>
35. , E. (2018) Erythrocyte deformability and eryptosis during inflammation, and impaired blood rheology. Clin. Hemorheol. Microcirc. 69, 545-550.
<https://doi.org/10.3233/CH-189205>
36. , E. W., Ge, D. T., Kong, S.-K. (2012) Salidroside protects human erythrocytes against hydrogen peroxide-induced apoptosis. J. Nat. Prod. (Gorakhpur) 75, 531–537.
<https://doi.org/10.1021/np200555s>
37. , S., Ferru, E., Blasi, B. et al. (2012) Oxidative stress and caspase-mediated fragmentation of cytoplasmic domain of erythrocyte band 3 during blood storage. Blood Transfus. 10 (Suppl. 2), s55-s62.
38. , I. P., Bjørås, M., Franzyk, H. et al. (2023) Optimization of the hemolysis assay for the assessment of cytotoxicity. Int. J. Mol. Sci. 24, 2914.
<https://doi.org/10.3390/ijms24032914>
39. , T., Jilani, K., Parveen, K. et al. (2022) Induction of erythrocyte membrane blebbing by methotrexate-induced oxidative stress. Dose Response 20, 15593258221093852.
<https://doi.org/10.1177/15593258221093853>
40. , Y. Y., Johnson, R. J. (2008) Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 27, 608-619.
<https://doi.org/10.1080/15257770802138558>
41. , B. I. M., Nascimento, E. A., Silva, C. J. et al. (2021a) Anticancer activity of monoterpenes: a systematic review. Mol. Biol. Rep. 48, 5775-5785.
<https://doi.org/10.1007/s11033-021-06578-5>
42. , B. O., Orlando, J. B., Pires, C. L. et al. (2021b) Genotoxicity induced by nerol, an essential oil present in citric plants using human peripheral blood mononuclear cells (PBMC) and HepG2/C3A cells as a model. J. Toxicol. Environ. Health A 84, 518-528.
<https://doi.org/10.1080/15287394.2021.1902443>
43. , G. D. S. E., Marques, J. N. J., Linhares, E. P. M. et al. (2022) Review of anticancer activity of monoterpenoids: geraniol, nerol, geranial and neral. Chem. Biol. Interact. 362, 109994.
<https://doi.org/10.1016/j.cbi.2022.109994>
44. , Chowdhary, S., Kumar, D. et al. (2022) Whether heparin causes hemolysis: an in silico and in vitro study. Indian J. Thorac. Cardiovasc. Surg. 38, 566-569.
<https://doi.org/10.1007/s12055-022-01340-3>
45. , R. R., Da Silva, A. M., Siqueira, R. P. et al. (2019) Synthesis of nerol derivatives containing a 1,2,3-triazole moiety and evaluation of their activities against cancer cell lines. J. Braz. Chem. Soc. 30, 541-561.
46. , J., Gan, Y., Pan, C. et al. (2018) Nerol-induced apoptosis associated with the generation of ROS and Ca2+ overload in saprotrophic fungus Aspergillus flavus. Appl. Microbiol. Biotechnol. 102, 6659-6672.
<https://doi.org/10.1007/s00253-018-9125-z>
47. , A. (2024) Apoptosis and eryptosis: similarities and differences. Apoptosis 29, 482-502.
<https://doi.org/10.1007/s10495-023-01915-4>
48. , A., Alfhili, M. A., Alsughayyir, J. et al. (2025) Current understanding of eryptosis: mechanisms, physiological functions, role in disease, pharmacological applications, and nomenclature recommendations. Cell Death Dis. 16, 467.
<https://doi.org/10.1038/s41419-025-07784-w>
49. , A., Havranek, O. (2024) Erythronecroptosis: an overview of necroptosis or programmed necrosis in red blood cells. Mol. Cell. Biochem. 479, 3273-3291.
<https://doi.org/10.1007/s11010-024-04948-8>
50. , A., Onishchenko, A. (2023) Casein kinase 1α mediates eryptosis: a review. Apoptosis 28, 1-19.
<https://doi.org/10.1007/s10495-022-01776-3>
51. , C., Catan, A., Guerin-Dubourg, A. et al. (2020) Enhanced oxidative stress and damage in glycated erythrocytes. PLoS One 15, e0235335.
<https://doi.org/10.1371/journal.pone.0235335>
52. , Y., Hosokawa, M., Kurihara, H. et al. (2008) Synthesis of phosphatidylated-monoterpene alcohols catalyzed by phospholipase D and their antiproliferative effects on human cancer cells. Bioorg. Med. Chem. Lett. 18, 4044-4046.
<https://doi.org/10.1016/j.bmcl.2008.05.113>
53. , W.-N., Lai, Y.-J., Ma, J.-W. et al. (2019) Citronellol induces necroptosis of human lung cancer cells via TNF-α pathway and reactive oxygen species accumulation. In Vivo 33, 1193-1201.
<https://doi.org/10.21873/invivo.11590>
54. , M., Feder-Kubis, J. (2020) Monoterpenes and their derivatives – recent development in biological and medical applications. Int. J. Mol. Sci. 21, 7078.
<https://doi.org/10.3390/ijms21197078>
55. , M., Pietrusiak, P., Feder-Kubis, J. (2021) Selected monocyclic monoterpenes and their derivatives as effective anticancer therapeutic agents. Int. J. Mol. Sci. 22, 4763.
<https://doi.org/10.3390/ijms22094763>
