Background: The progressive course of coronavirus disease 2019 (COVID-19) is more frequently observed in individuals with obesity, diabetes, pulmonary and cardiovascular disease, or arterial hypertension. Many patients with these conditions are prescribed statins to treat hypercholesterolaemia. However, statins exhibit additional pleiotropic effects. The present study aims to investigate the effects of all eight currently existing statins on the expression of genes whose products have been reported to be directly associated with complicated COVID-19 disease. Methods: We extended the interpretation of the whole-genome DNA microarray analyses of pancreatic cancer cells MiaPaCa-2 and whole-transcriptome analyses of adipose tissue-derived mesenchymal stem cells AD-MSC that we had performed in the past. From the number of genes with altered expression induced by statins, we focused on those reported to be involved in a complicated course of COVID-19, including APOE and ACE2, genes encoding proteins involved in innate antiviral immunity and respiratory failure genes. Results: Although we did not observe statin-induced changes in the expression of APOE, ACE2 and any of the six genes clustered in the locus associated with respiratory failure in patients with COVID-19, some statins induced changes in the expression of genes encoding their interaction partners. Among genes associated with the immune system, all statins, which are effective in vitro affected the expression of genes encoding IL-6 and IL-8 and interaction partners of NF-kB, which may influence the duration of viral persistence. Conclusions: Statins act on multiple pathways simultaneously, some of which support COVID-19 development, while others suppress it.

Central Animal Facility Jessenius Faculty of Medicine in Martin Comenius University Malá Hora 4D 036 01 Martin Slovakia

Department of Biochemistry and Microbiology Faculty of Food and Biochemical Technology University of Chemistry and Technology Prague Technická 3 166 28 Prague Czech Republic

Department of Informatics and Chemistry University of Chemistry and Technology Prague Technická 3 166 28 Prague Czech Republic

Department of Medical Biochemistry Jessenius Faculty of Medicine in Martin Comenius University Malá Hora 4 036 01 Marti Slovakia

Institute of Medical Biology Genetics and Clinical Genetics Faculty of Medicine Comenius University Sasinkova 4 811 08 Bratislava Slovakia

Laboratory Diagnostics Institute of Medical Biochemistry 4th Department of Internal Medicine General University Hospital Prague 1st Faculty of Medicine Charles University Kateřinská 1660 32 121 08 Prague Czech Republic

Laboratory of Genomics and Bioinformatics Institute of Molecular Genetics The Czech Academy of Science Vídeňská 1083 142 20 Prague Czech Republic

Zobrazit více v PubMed

Severe COVID-19 GWAS Group. Ellinghaus D. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N. Engl. J. Med. 2020;383:1522–1534. doi: 10.1056/NEJMoa2020283. PubMed DOI PMC

Noureddine F.Y., Chakkour M. The Emergence of SARS-CoV-2 Variant(s) and Its Impact on the Prevalence of COVID-19 Cases in the Nabatieh Region, Lebanon. Med. Sci. 2021;9:40. doi: 10.3390/medsci9020040. PubMed DOI PMC

Šúri T., Pfeiferová L. Developing molecular surveillance of SARS-CoV-2 in the Czech Republic (2021–2022) Sci. Rep. 2025;15:19690. doi: 10.1038/s41598-025-01074-3. PubMed DOI PMC

World Health Organization Coronavirus Disease (COVID-19) 2020. [(accessed on 12 November 2020)]. Available online: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/question-and-answers-hub/q-a-detail/coronavirus-disease-covid-19.

Toth P.P., Banach M. Statins: Then and now. Methodist DeBakey Cardiovasc. J. 2019;15:23–31. doi: 10.14797/mdcj-15-1-23. PubMed DOI PMC

De Spiegeleer A., Bronselaer A. The effects of ARBs, ACEis, and statins on clinical outcomes of COVID-19 infection among nursing home residents. J. Am. Med. Dir. Assoc. 2020;21:909–914. doi: 10.1016/j.jamda.2020.06.018. PubMed DOI PMC

Daniels L.B., Sitapati A.M. Relation of statin use prior to admission to severity and recovery among COVID-19 inpatients. Am. J. Cardiol. 2020;136:149–155. doi: 10.1016/j.amjcard.2020.09.012. PubMed DOI PMC

Zhang X.J., Qin J.J. In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19. Cell Metab. 2020;32:176–187. doi: 10.1016/j.cmet.2020.06.015. PubMed DOI PMC

Kow C.S., Hasan S.S. Meta-analysis of effect of statins in patients with COVID-19. Am. J. Cardiol. 2020;134:153–155. doi: 10.1016/j.amjcard.2020.08.004. PubMed DOI PMC

Diaz-Arocutipa C., Melgar-Talavera B. Statins reduce mortality in patients with COVID-19: An updated meta-analysis of 147,824 patients. Int. J. Infect. Dis. 2021;110:374–381. doi: 10.1016/j.ijid.2021.08.004. PubMed DOI PMC

Kow C.S., Hasan S.S. The association between the use of statins and clinical outcomes in patients with COVID-19: A systematic review and meta-analysis. Am. J. Cardiovasc. Drugs. 2022;22:295–304. doi: 10.1007/s40256-021-00490-w. PubMed DOI PMC

Florêncio de Mesquita C., Rivera A. Adjunctive Statin Therapy in Patients with Covid-19: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Am. J. Med. 2024;137:697–705. doi: 10.1016/j.amjmed.2024.06.002. PubMed DOI

Ayeh S.K., Abbey E.J. Statins use and COVID-19 outcomes in hospitalized patients. PLoS ONE. 2021;16:e0256899. doi: 10.1371/journal.pone.0256899. PubMed DOI PMC

Shrestha S. Statin drug therapy may increase COVID-19 infection. NMJ. 2020;3:326–327. doi: 10.3126/nmj.v3i1.28256. DOI

Peymani P., Dehesh T. Statins in patients with COVID-19: A retrospective cohort study in Iranian COVID-19 patients. Transl. Med. Commun. 2021;6:3. doi: 10.1186/s41231-021-00082-5. PubMed DOI PMC

Focosi D., Franchini M. COVID-19 therapeutics. Clin. Microbiol. Rev. 2024;37:e0011923. doi: 10.1128/cmr.00119-23. PubMed DOI PMC

Dashti-Khavidaki S., Khalili H. Considerations for statin therapy in patients with COVID-19. Pharmacotherapy. 2020;40:484–486. doi: 10.1002/phar.2397. PubMed DOI PMC

Guan W.J., Ni Z.Y. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020;382:1708–1720. doi: 10.1056/NEJMoa2002032. PubMed DOI PMC

Conti P., Ronconi G. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVID-19 or SARS-CoV-2): Anti-inflammatory strategies. J. Biol. Regul. Homeost. Agents. 2020;34:327–331. PubMed

Gorabi A.M., Kiaie N. Antiviral effects of statins. Pharmacol. Res. :2020. doi: 10.1016/j.plipres.2020.101054. PubMed DOI

Superti F., Seganti L. SA-11 rotavirus binding to human serum lipoproteins. Med. Microbiol. Immunol. 1992;181:77–86. doi: 10.1007/BF00189426. PubMed DOI

Wang H., Yang P. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res. 2008;18:290–301. doi: 10.1038/cr.2008.15. PubMed DOI PMC

Moeller R., Zapatero-Belinchón F. Effect of statins on SARS-CoV-2 infection. J. medRxiv. 2020;13:20152272. doi: 10.1101/2020.07.13.20152272. DOI

Shang J., Wan Y. Cell entry mechanisms of SARS-CoV-2. Proc. Natl. Acad. Sci. USA. 2020;117:11727–11734. doi: 10.1073/pnas.2003138117. PubMed DOI PMC

Jackson C.B., Farzan M., Chen B., Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell Biol. 2022;23:3–20. doi: 10.1038/s41580-021-00418-x. PubMed DOI PMC

DeDiego M.L., Nieto-Torres J.L. Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival. J. Virol. 2014;88:913–924. doi: 10.1128/JVI.02576-13. PubMed DOI PMC

Totura A.L., Whitmore A. Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. Mbio. 2015;6:10–1128. doi: 10.1128/mBio.00638-15. PubMed DOI PMC

Totura A.L., Baric R.S. Reply to “Statins may decrease the fatality rate of MERS infection”. Mbio. 2015;6:10–1128. doi: 10.1128/mBio.01303-15. PubMed DOI PMC

Tudorache I.F., Trusca V.G. Apolipoprotein E–A multifunctional protein with implications in various pathologies as a result of its structural features. Comput. Struct. Biotechnol. J. 2017;15:359–365. doi: 10.1016/j.csbj.2017.05.003. PubMed DOI PMC

Kuo C.L., Pilling L.C. APOE e4 genotype predicts severe COVID-19 in the UK Biobank community cohort. J. Gerontol. A Biol. Sci. Med. Sci. 2020;75:2231–2232. doi: 10.1093/gerona/glaa131. PubMed DOI PMC

Gbelcová H., Rimpelová S. Variability in statin-induced changes in gene expression profiles of pancreatic cancer. Sci. Rep. 2017;7:44219. doi: 10.1038/srep44219. PubMed DOI PMC

Gbelcová H., Rimpelová S. Highly variable biological effects of statins on cancer, non-cancer, and stem cells in vitro. Sci. Rep. 2024;14:11830. doi: 10.1038/s41598-024-62615-w. PubMed DOI PMC

Brábek J., Jakubek M. Interleukin-6: Molecule in the intersection of cancer, ageing and COVID-19. Int. J. Mol. Sci. 2020;21:7937. doi: 10.3390/ijms21217937. PubMed DOI PMC

Katopodis P., Anikin V. Pan-cancer analysis of transmembrane protease serine 2 and cathepsin L that mediate cellular SARS CoV 2 infection leading to COVID-19. Int. J. Oncol. 2020;57:533–539. doi: 10.3892/ijo.2020.5071. PubMed DOI PMC

Zhang Z., Li L. The SARS-CoV-2 host cell receptor ACE2 correlates positively with immunotherapy response and is a potential protective factor for cancer progression. Comput. Struct. Biotechnol. J. 2020;18:2438–2444. doi: 10.1016/j.csbj.2020.08.024. PubMed DOI PMC

Sánchez-Guijo F., García-Arranz M. Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation: A proof of concept study. eClinicalMedicine. 2020;25:100454. doi: 10.1016/j.eclinm.2020.100454. PubMed DOI PMC

Gbelcová H., Lenícek M. Differences in antitumor effects of various statins on human pancreatic cancer. Int. J. Cancer. 2008;122:1214–1221. doi: 10.1002/ijc.23242. PubMed DOI

Durinck S., Moreau Y. BioMart and Bioconductor: A powerful link between biological databases and microarray data analysis. Bioinformatics. 2005;21:3439–3440. doi: 10.1093/bioinformatics/bti525. PubMed DOI

Hubbard T.J., Aken B.L. Ensembl 2007. Nucleic Acids Res. 2007;35:D610–D617. doi: 10.1093/nar/gkl996. PubMed DOI PMC

Carvalho B.S., Irizarry R.A. A framework for oligonucleotide microarray preprocessing. Bioinformatics. 2010;26:2363–2367. doi: 10.1093/bioinformatics/btq431. PubMed DOI PMC

R Core Team R: A Language and Environment for Statistical Computing; R Foundation for Statistical Computing. 2021. [(accessed on 20 February 2021)]. Available online: https://www.R-project.org/

Ritchie M.E., Phipson B. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47. doi: 10.1093/nar/gkv007. PubMed DOI PMC

Storey J.D., Tibshirani R. Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA. 2003;100:9440–9445. doi: 10.1073/pnas.1530509100. PubMed DOI PMC

Bustin S.A., Benes V., Garson J.A., Hellemans J., Huggett J., Kubista M., Mueller R., Nolan T., Pfaffl M.W., Shipley G.L., et al. The MIQE Guidelines: M inimum I nformation for Publication of Q uantitative Real-Time PCR E xperiments. Clin. Chem. 2009;55:611–622. doi: 10.1373/clinchem.2008.112797. PubMed DOI

Jensen L.J., Kuhn M. STRING 8–a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res. 2009;37:D412–D416. doi: 10.1093/nar/gkn760. PubMed DOI PMC

Rice G.I., Thomas D.A. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2, and neprilysin in angiotensin peptide metabolism. Biochem. J. 2004;383:45–51. doi: 10.1042/BJ20040634. PubMed DOI PMC

Velazquez-Salinas L., Verdugo-Rodriguez A. The role of interleukin 6 during viral infections. Front. Microbiol. 2019;10:1057. doi: 10.3389/fmicb.2019.01057. PubMed DOI PMC

Lee J.H., Sergi C., Kast R.E. Basic implications on three pathways associated with SARS-CoV-2. Biomed. J. 2024;47:100766. doi: 10.1016/j.bj.2024.100766. PubMed DOI PMC

Zou M., Su X. The molecular mechanism of multiple organ dysfunction and targeted intervention of COVID-19 based on time-order transcriptomic analysis. Front. Immunol. 2021;12:729776. doi: 10.3389/fimmu.2021.729776. PubMed DOI PMC

Rimpelová S., Kolář M. Comparison of transcriptomic profiles of MiaPaCa-2 pancreatic cancer cells treated with different statins. Molecules. 2021;26:3528. doi: 10.3390/molecules26123528. PubMed DOI PMC

Nguyen T.B., Sakata-Yanagimoto M. Dasatinib is an effective treatment for angioimmunoblastic T-cell lymphoma. Cancer Res. 2020;80:1875–1884. doi: 10.1158/0008-5472.CAN-19-2787. PubMed DOI

Tanaka K., Matsumoto Y. Impact of RhoA overexpression on clinical outcomes in cervical squamous cell carcinoma treated with concurrent chemoradiotherapy. J. Radiat. Res. 2020;61:221–230. doi: 10.1093/jrr/rrz093. PubMed DOI PMC

Bros M., Haas K. RhoA as a key regulator of innate and adaptive immunity. Cells. 2019;8:733. doi: 10.3390/cells8070733. PubMed DOI PMC

Liu D., Mei X. RhoA inhibits apoptosis and increases proliferation of cultured SPCA1 lung cancer cells. J. Mol. Med. 2017;15:3963–3968. doi: 10.3892/mmr.2017.6545. PubMed DOI PMC

Ozkan S., Cakmak F. Efficacy of serum angiotensin II levels in prognosis of patients with coronavirus disease 2019. Crit. Care Med. 2021;49:e613–e623. doi: 10.1097/CCM.0000000000004967. PubMed DOI

Eleuteri D., Montini L. Renin-angiotensin system dysregulation in critically ill patients with acute respiratory distress syndrome due to COVID-19: A preliminary report. Crit. Care. 2021;25:91. doi: 10.1186/s13054-021-03507-7. PubMed DOI PMC

Miesbach W. Pathological Role of Angiotensin II in Severe COVID-19. TH Open. 2020;4:e138–e144. doi: 10.1055/s-0040-1713678. PubMed DOI PMC

Zoufaly A., Poglitsch M. Human recombinant soluble ACE2 in severe COVID-19. Lancet Respir. Med. 2020;8:1154–1158. doi: 10.1016/S2213-2600(20)30418-5. PubMed DOI PMC

Abd El-Aziz T.M., Al-Sabi A. Human recombinant soluble ACE2 (hrsACE2) shows promise for treating severe COVID-19. Signal Transduct. Target. Ther. 2020;5:258. doi: 10.1038/s41392-020-00374-6. PubMed DOI PMC

Li Y.H., Wang Q.X. Effects of rosuvastatin on expression of angiotensin-converting enzyme 2 after vascular balloon injury in rats. J. Geriatr. Cardiol. 2013;10:151–158. PubMed PMC

Minz M., Bansal M. Statins and SARS-CoV-2 disease: Current concepts and possible benefits. Diabetes Metab. Syndr. 2020;14:2063–2067. doi: 10.1016/j.dsx.2020.10.021. PubMed DOI PMC

Wang H., Yuan Z. Cholesterol and COVID-19 lethality in elderly. bioRxiv. 2020 doi: 10.1101/2020.05.09.086249. DOI

Fuior E.V., Gafencu A.V. Apolipoprotein C1: Its pleiotropic effects in lipid metabolism and beyond. Int. J. Mol. Sci. 2019;20:5939. doi: 10.3390/ijms20235939. PubMed DOI PMC

Subir R., Jagat J.M. Pros and cons for use of statins in people with coronavirus disease-19 (COVID-19) Diabetes Metab. Syndr. 2020;14:1225–1229. doi: 10.1016/j.dsx.2020.07.011. PubMed DOI PMC

Rodrigues-Diez R.R., Tejera-Muñoz A. Statins: Could an old friend help in the fight against COVID-19? Br. J. Pharmacol. 2020;177:4873–4886. doi: 10.1111/bph.15166. PubMed DOI PMC

Chansrichavala P., Chantharaksri U. Atorvastatin attenuates TLR4-mediated NF-κB activation in a MyD88-dependent pathway. Asian Pac. J. Allergy Immunol. 2009;27:49–57. PubMed

Gubernatorova E., Gorshkova E. IL-6: Relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor. Rev. 2020;53:12–24. doi: 10.1016/j.cytogfr.2020.05.009. PubMed DOI PMC

Coomes E.A., Haghbayan H. Interleukin-6 in COVID-19: A systematic review and meta-analysis. Rev. Med. Virol. 2020;30:1–9. doi: 10.1002/rmv.2141. PubMed DOI PMC

Toniati P., Piva S. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single-center study of 100 patients in Brescia, Italy. Autoimmun. Rev. 2020;19:102568. doi: 10.1016/j.autrev.2020.102568. PubMed DOI PMC

Salvarani C., Dolci G. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern. Med. 2021;181:24–31. doi: 10.1001/jamainternmed.2020.6615. PubMed DOI PMC

Veiga V.C., Prats J.A.G.G. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: Randomised controlled trial. BMJ. 2021;372:n84. doi: 10.1136/bmj.n84. PubMed DOI PMC

Hermine O., Mariette X. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern. Med. 2021;181:32–40. doi: 10.1001/jamainternmed.2020.6820. PubMed DOI PMC

Stone J.H., Frigault M.J. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N. Engl. J. Med. 2020;383:2333–2344. doi: 10.1056/NEJMoa2028836. PubMed DOI PMC

Campbell G.R., To R.K. SARS-CoV-2, SARS-CoV-1, and HIV-1 derived ssRNA sequences activate the NLRP3 inflammasome in human macrophages through a non-classical pathway. iScience. 2021;24:102295. doi: 10.1016/j.isci.2021.102295. PubMed DOI PMC

Onodi F., Bonnet-Madin L. SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4. J. Exp. Med. 2021;218:e20201387. doi: 10.1084/jem.20201387. PubMed DOI PMC