Original Articles

Computational identification of plant microRNAs targeting Plasmodium falciparum: a new strategy to address the challenges of modern malaria treatment

Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 3 October 2025
389
Views
148
Downloads

Authors

Malaria remains one of the greatest challenges to global health, with Plasmodium falciparum responsible for the majority of severe cases and deaths, despite significant progress in diagnosis and treatment. Resistance to antimalarial drugs, particularly associated with P. falciparum kelch13 (PfK13) mutations in Africa, as well as resistance to partner drugs such as piperaquine and lumefantrine, and limited efficacy of vaccines, necessitate the search for new therapeutic approaches. This review analyzes the current challenges in malaria treatment, focusing on the role of microRNAs (miRNAs) as potential regulators of the immune response and potential therapeutic targets. Special attention is paid to the computational screening of plant miRNAs that have promise in suppressing the expression of parasitic genes in P. falciparum. We reviewed recent literature on the molecular mechanisms of antimalarial drug resistance and the potential applications of miRNAs in malaria therapy, focusing on host- and parasite-derived miRNAs, their roles in pathogenesis, and experimental therapeutic strategies, including nanoparticle-mediated miRNA delivery. Emerging data indicate that specific host miRNAs (e.g., miR-451, miR-223) can modulate erythrocytic invasion, inflammatory responses, and disease outcomes. In parallel, advances in RNA-based therapeutics demonstrate the feasibility of miRNA mimics and inhibitors as adjunctive tools to complement existing antimalarial regimens. The integration of miRNA-based approaches into malaria therapy represents a promising frontier that could overcome the limitations of conventional drug-based strategies. Future research should prioritize the functional characterization of miRNAs, optimization of delivery systems, and evaluation of combinatorial therapies to enhance clinical translation.

Downloads

Download data is not yet available.

Citations

World Health Organization. World Malaria Report 2024: addressing inequity in the global malaria response. Geneva: WHO; 2024.
Sidhu AB, Verdier-Pinard D, Fidock DA. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 2002;298:210-3. DOI: https://doi.org/10.1126/science.1074045
Ndiaye D, Daily JP, Sarr O, et al. Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase genes in Senegal. Trop Med Int Health 2005;10:1176-9. DOI: https://doi.org/10.1111/j.1365-3156.2005.01506.x
Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009;361:455-67. DOI: https://doi.org/10.1056/NEJMoa0808859
Assefa A, Fola AA, Tasew G. Emergence of Plasmodium falciparum strains with artemisinin partial resistance in East Africa and the Horn of Africa: is there a need to panic? Malar J 2024;23:34. DOI: https://doi.org/10.1186/s12936-024-04848-8
Baird JK, Valecha N, Duparc S, et al. Diagnosis and Treatment of Plasmodium vivax Malaria. Am J Trop Med Hyg 2016;95:35-51. DOI: https://doi.org/10.4269/ajtmh.16-0171
Recht J, Ashley EA, White NJ. Use of primaquine and glucose-6-phosphate dehydrogenase deficiency testing: Divergent policies and practices in malaria endemic countries. PLoS Negl Trop Dis 2018;12:e0006230. DOI: https://doi.org/10.1371/journal.pntd.0006230
Croft AM. A lesson learnt: the rise and fall of Lariam and Halfan. J R Soc Med 2007;100:170-4. DOI: https://doi.org/10.1177/014107680710011411
Haeusler IL, Chan XHS, Guérin PJ, et al. The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review. BMC Med 2018;16:200. DOI: https://doi.org/10.1186/s12916-018-1188-2
RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 2015;386:31-45. DOI: https://doi.org/10.1016/S0140-6736(15)60721-8
Datoo MS, Dicko A, Tinto H, et al. Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial. Lancet 2024;403:533-44. DOI: https://doi.org/10.1016/S0140-6736(23)02511-4
Sallam M, Al-Khatib AO, Al-Mahzoum KS, et al. Current Developments in Malaria Vaccination: A Concise Review on Implementation, Challenges, and Future Directions. Clin Pharmacol 2025;17:29-47. DOI: https://doi.org/10.2147/CPAA.S513282
Ruisch A, Iodice M, Mathur I, et al. Systematic review on the cost of seasonal malaria chemoprevention (SMC). Malar J 2024;23:384. DOI: https://doi.org/10.1186/s12936-024-05217-1
Uwimana A, Legrand E, Stokes BH, et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat Med 2020;26:1602-8. DOI: https://doi.org/10.1038/s41591-020-1005-2
Nguyen TD, Tran TN, Parker DM, et al. Antimalarial mass drug administration in large populations and the evolution of drug resistance. PLOS Glob Public Health 2023;3:e0002200. DOI: https://doi.org/10.1371/journal.pgph.0002200
Nayyar GML, Breman JG, Mackey TK, et al. Falsified and Substandard Drugs: Stopping the Pandemic. Am J Trop Med Hyg 2019;100:1058-65. DOI: https://doi.org/10.4269/ajtmh.18-0981
Kataria P, Surela N, Chaudhary A, Das J. MiRNA: Biological Regulator in Host-Parasite Interaction during Malaria Infection. Int J Environ Res Public Health 2022;19:2395. DOI: https://doi.org/10.3390/ijerph19042395
Wu Y, Leyk S, Torabi H, et al. Plasmodium falciparum infection reshapes the human microRNA profiles of red blood cells and their extracellular vesicles. iScience 2023;26:107119. DOI: https://doi.org/10.1016/j.isci.2023.107119
Yu W, Wang S, Wang Y, et al. MicroRNA: role in macrophage polarization and the pathogenesis of the liver fibrosis. Front Immunol 2023;14:1147710. DOI: https://doi.org/10.3389/fimmu.2023.1147710
Cohen A, Zinger A, Tiberti N, et al. Differential plasma microvesicle and brain profiles of microRNA in experimental cerebral malaria. Malar J 2018;17:192. DOI: https://doi.org/10.1186/s12936-018-2330-5
Gupta H, Wassmer SC. Harnessing the Potential of miRNAs in Malaria Diagnostic and Prevention. Front Cell Infect Microbiol 2021;11:793954. DOI: https://doi.org/10.3389/fcimb.2021.793954
Oxendine Harp K, Bashi A, Botchway F, et al. MicroRNAs miR-451a and Let-7i-5p Profiles in Circulating Exosomes Vary among Individuals with Different Sickle Hemoglobin Genotypes and Malaria. J Clin Med 2022;11:500. DOI: https://doi.org/10.3390/jcm11030500
LaMonte G, Philip N, Reardon J, et al. Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance. Cell Host Microbe 2012;12:187-99. DOI: https://doi.org/10.1016/j.chom.2012.06.007
He X, Pan W. Host-parasite interactions mediated by cross-species microRNAs. Trends Parasitol 2022;38:478-88. DOI: https://doi.org/10.1016/j.pt.2022.02.011
Walzer KA, Chi JT. Trans-kingdom small RNA transfer during host-pathogen interactions: The case of P. falciparum and erythrocytes. RNA Biol 2017;14:442-9. DOI: https://doi.org/10.1080/15476286.2017.1294307
Mehrotra S, Kupani M, Pandey RK. Chapter 12 - Therapeutic potential of miRNAs in parasitic infectious diseases. Academic Press; 2024, pp. 265-291. DOI: https://doi.org/10.1016/B978-0-323-99661-7.00011-4
Sikka R, Bharti PK, Gupta H. microRNAs: An opportunity to overcome significant challenges in malaria detection and control. Curr Res Pharmacol Drug Discov 2022;3:100115. DOI: https://doi.org/10.1016/j.crphar.2022.100115
Smith TF, Waterman MS. Identification of common molecular subsequences. J Mol Biol 1981;147:195-7. DOI: https://doi.org/10.1016/0022-2836(81)90087-5
Zuker M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 2003;31:3406-15. DOI: https://doi.org/10.1093/nar/gkg595
Baum J, Papenfuss AT, Mair GR, et al. Molecular genetics and comparative genomics reveal RNAi is not functional in malaria parasites. Nucleic Acids Res 2009;37:3788-98. DOI: https://doi.org/10.1093/nar/gkp239
Mueller AK, Hammerschmidt-Kamper C, Kaiser A. RNAi in Plasmodium. Curr Pharm Des 2014;20:278-83. DOI: https://doi.org/10.2174/13816128113199990027
Wang Z, Xi J, Hao X, et al. Red blood cells release microparticles containing human argonaute 2 and miRNAs to target genes of Plasmodium falciparum. Emerg Microbes Infect 2017;6:e75. DOI: https://doi.org/10.1038/emi.2017.63
Rathjen T, Nicol C, McConkey G, Dalmay T. Analysis of short RNAs in the malaria parasite and its red blood cell host. FEBS Lett 2006;580:5185-8. DOI: https://doi.org/10.1016/j.febslet.2006.08.063
Eldem V, Çelikkol Akçay U, Ozhuner E, et al. Genome-Wide Identification of miRNAs Responsive to Drought in Peach (Prunus persica) by High-Throughput Deep Sequencing. PLOS ONE 2012;7:e50298. DOI: https://doi.org/10.1371/journal.pone.0050298
Liu D, Song Y, Chen Z, Yu D. Ectopic expression of miR396 suppresses GRF target gene expression and alters leaf growth in Arabidopsis. Physiol Plant 2009;136:223-36. DOI: https://doi.org/10.1111/j.1399-3054.2009.01229.x
Sunkar R, Li YF, Jagadeeswaran G. Functions of microRNAs in plant stress responses. Trends Plant Sci 2012;17:196-203. DOI: https://doi.org/10.1016/j.tplants.2012.01.010
Kozomara A, Birgaoanu M, Griffiths-Jones S. miRBase: from microRNA sequences to function. Nucleic Acids Res 2019;47:D155-62. DOI: https://doi.org/10.1093/nar/gky1141
Sripathi Venkateswara R, Yongwook C, Zachary B, et al. Identification of MicroRNAs and Their Targets in Four Gossypium Species Using RNA Sequencing. Curr Plant Biol 2018;14:30-40. DOI: https://doi.org/10.1016/j.cpb.2018.09.008
Li JB, Ding J, Yu X, et al. Identification and Expression Analysis of Critical MicroRNA-Transcription Factor Regulatory Modules Related to Seed Development and Oil Accumulation in Developing Hippophae Rhamnoides Seeds. Industrial Crops and Products 2019;137:33-42. DOI: https://doi.org/10.1016/j.indcrop.2019.05.011
Baek D, Chun HJ, Kang S, et al. A Role for Arabidopsis miR399f in Salt, Drought, and ABA Signaling. Mol Cells 2016;39:111-8. DOI: https://doi.org/10.14348/molcells.2016.2188
Kyrollos DG, Reid B, Dick K, et al. RPmirDIP: Reciprocal Perspective improves miRNA targeting prediction. Sci Rep 2020;10:11770. DOI: https://doi.org/10.1038/s41598-020-68251-4
Bachmann A, Metwally NG, Allweier J, et al. CD36-A Host Receptor Necessary for Malaria Parasites to Establish and Maintain Infection. Microorganisms 2022;10:2356. DOI: https://doi.org/10.3390/microorganisms10122356
Thiam A, Nisar S, Adjemout M, et al. ATP2B4 regulatory genetic variants are associated with mild malaria. Malar J 2023;22:68. DOI: https://doi.org/10.1186/s12936-023-04503-8
Oyong DA, Loughland JR, SheelaNair A, et al. Loss of complement regulatory proteins on red blood cells in mild malarial anaemia and in Plasmodium falciparum induced blood-stage infection. Malar J 2019;18:312. DOI: https://doi.org/10.1186/s12936-019-2962-0
Yamagishi J, Natori A, Tolba ME, et al. Interactive transcriptome analysis of malaria patients and infecting Plasmodium falciparum. Genome Res 2014;24:1433-44. DOI: https://doi.org/10.1101/gr.158980.113
Liu M, Dickinson-Copeland C, Hassana S, Stiles JK. Plasmodium-infected erythrocytes (pRBC) induce endothelial cell apoptosis via a heme-mediated signaling pathway. Drug Des Devel Ther 2016;10:1009-18. DOI: https://doi.org/10.2147/DDDT.S96863
Ahmed MZ, Bhardwaj N, Sharma S, et al. Transcriptional Modulation of the Host Immunity Mediated by Cytokines and Transcriptional Factors in Plasmodium falciparum-Infected Patients of North-East India. Biomolecules 2019;9:600. DOI: https://doi.org/10.3390/biom9100600
Sharma M, Singh U. Role of tRNA-Derived Fragments in Protozoan Parasite Biology. Cells 2025;14:115. DOI: https://doi.org/10.3390/cells14020115
Wang Z, Wei C, Hao X, et al. Genome-wide identification and characterization of transfer RNA-derived small RNAs in Plasmodium falciparum. Parasit Vectors 2019;12:36. DOI: https://doi.org/10.1186/s13071-019-3301-6
Keam SP, Hutvagner G. tRNA-Derived Fragments (tRFs): Emerging New Roles for an Ancient RNA in the Regulation of Gene Expression. Life (Basel) 2015;5:1638-51. DOI: https://doi.org/10.3390/life5041638
Kumar P, Anaya J, Mudunuri SB, et al. Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets. BMC Biol 2014;12:78. DOI: https://doi.org/10.1186/PREACCEPT-5867533061403216
Saikia M, Hatzoglou M. The many virtues of tRNA-derived stress-induced RNAs (tiRNAs): discovering novel mechanisms of stress response and effect on human health. J Biol Chem 2015;290:29761-8. DOI: https://doi.org/10.1074/jbc.R115.694661
Weng Q, Wang Y, Xie Y, et al. Extracellular vesicles-associated tRNA-derived fragments (tRFs): biogenesis, biological functions, and their role as potential biomarkers in human diseases. J Mol Med 2022;100:679-95. DOI: https://doi.org/10.1007/s00109-022-02189-0
Shi L, Guo C, Fang M, et al. Cross-kingdom regulation of plant microRNAs: potential application in crop improvement and human disease therapeutics. Front Plant Sci 2024;15:1512047. DOI: https://doi.org/10.3389/fpls.2024.1512047
Wang W, Liu D, Zhang X, et al. Plant MicroRNAs in Cross-Kingdom Regulation of Gene Expression. Int J Mol Sci 2018;19:2007. DOI: https://doi.org/10.3390/ijms19072007
Yang L, Feng H. Cross-kingdom regulation by plant-derived miRNAs in mammalian systems. Animal Model Exp Med 2023;6:518-25. DOI: https://doi.org/10.1002/ame2.12358
Dmitri Koroliouk, Institute of Telecommunications and Global Information Space of the National Academy of Sciences of Ukraine, Kyiv

Interdepartmental Center for Comparative Medicine, Alternative Techniques, and Aquaculture, University of Rome Tor Vergata, Italy; Department of Microelectronics, Faculty of Electronics, National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic; Institute”, Kyiv, Ukraine; Institute of Mathematics of the National Academy of Sciences of Ukraine, Kyiv, Ukraine.

Giacomo Maria Paganotti, Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia

Botswana-University of Pennsylvania Partnership, Gaborone, Botswana.

Vittorio Colizzi, UNESCO Chair in Interdisciplinary Biotechnology, University of Rome Tor Vergata; Eurobiopark, Tor Vergata Foundation, University of Rome Tor Vergata

Faculty of Medicine, University Hospital Complex “Bon Samaritain”, N’Djamena, Chad.

How to Cite



Computational identification of plant microRNAs targeting Plasmodium falciparum: a new strategy to address the challenges of modern malaria treatment. (2025). Sahelian Journal of Responsible One Health, 1(2). https://doi.org/10.4081/sjroh.2025.568