Statins beyond Lipid Lowering: A Narrative Review of Their Pleiotropic Anti-inflammatory Mechanisms through Lipid Metabolism, Immune Modulation, and Cell Signaling

Subject Areas : Journal of Chemical Health Risks

Peyman Bakhshaei Shahrebabaki ¹ , Raed Fanoukh Aboqader ² , Alizamen Salehifard Jouneghani ³ , Mukhayya Djumaniyazova Middle Khusinovna ⁴ , Alireza Salehifard Jouneghani ⁵ , Yuldoshev Jushkinbek Erkaboy ugli ⁶ , Umida Sadikova ⁷ , Norbek Kholboyev ⁸ , Farnaz Farzaneh Dehkordi ⁹ , Farhad Safarpoor Dehkordi ¹⁰

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Received: 2025-05-27 Accepted : 2025-08-17 Published : 2025-06-15

Keywords: Statins, Lipid metabolism inflammatory diseases Autoimmune, Cancer,

Abstract :

Statins, primarily known for their lipid-lowering properties, have emerged as significant agents in the field of anti-inflammatory and immunomodulatory therapies. This paper explores the pleiotropic effects of statins, which extend beyond cholesterol reduction, contributing to cardiovascular protection and potential therapeutic applications in various inflammatory and autoimmune diseases. The mechanisms by which statins exert these effects include the inhibition of isoprenoid-dependent signaling pathways, modulation of cytokine production, enhancement of endothelial function, and attenuation of immune cell activation. These actions are particularly relevant in conditions characterized by chronic inflammation, such as multiple sclerosis (MS) and neurodegenerative disorders. Research indicates that statins may mitigate the progression of MS, a disease marked by inflammation and myelin damage in the central nervous system, potentially offering protective benefits through their anti-inflammatory properties. Furthermore, studies have shown that statins can cross the blood-brain barrier, making them candidates for reducing neuroinflammation and delaying cognitive decline in diseases like Alzheimer's and Parkinson's. The findings suggest that statins could play a crucial role in managing not only cardiovascular diseases but also a range of inflammatory conditions, warranting further investigation into their full therapeutic potential beyond dyslipidemia. In conclusion, while statins are primarily prescribed for lowering cholesterol, their diverse mechanisms of action highlight their value in preventing and treating inflammatory conditions. This paper emphasizes the need for continued research to fully understand the implications of statins in various clinical settings, particularly in the context of chronic inflammatory diseases and neurodegenerative disorders’

References:

1. Milani E., Saeidi M.S., Gholizadeh H .,2017.Floristic, life form and chorological studies of the Abshar protected area, Shirgah, Mazandaran Province, north of Iran. Caspian Journal of Environmental Sciences. 15, 165–180. https://doi.org/10.22124/cjes.2017.2373
2. Sashindran N.K., 2007.Alteration in the primary metabolites in three different tissues of silkworm, Bombyx mori L. under the influence of a Juvenoid, R394. Caspian Journal of Environmental Sciences. 5, 27–33
3. Roitman R., Schatton W., Ilyich M.E .,2021.Evaluating the environmental and therapeutic impacts of dietary supplement (Case study: The supplement Oyox for prevention of environment damages, treatment and disorders in the hepatobilliary system). Caspian Journal of Environmental Sciences. 19, 495–502. https://doi.org/10.22124/cjes.2021.4935
4. Shojaeian A., Mehri-Ghahfarrokhi A., Banitalebi-Dehkordi M., 2020. Monophosphoryl Lipid A and Retinoic Acid Combinations Increased Germ Cell Differentiation Markers Expression in Human Umbilical Cord-derived Mesenchymal Stromal Cells in an In vitro Ovine Acellular Testis Scaffold. International Journal of Molecular and Cellular Medicine. https://doi.org/10.22088/IJMCM.BUMS.9.4.288
5. Aghabozorg Afjeh S.S., Ghaderian S.M.H., Mirfakhraie R., Piryaei M., Zaim K.H., 2014. Association Study of rs3184504 C>T Polymorphism in Patients With Coronary Artery Disease. International Journal of Molecular and Cellular Medicine. 3(3), 157-65.
6. Shojaee M., Golpasha M.F., Maliji G., ijani A., Aghajanpour M.S.M., Mousavi K.S.N., 2013. C-reactive protein levels in patients with periodontal disease and normal subjects. International Journal of Molecular and Cellular Medicine. 2,151
7. Bewicz-Binkowska D., Zgórzyńska E., Dziedzic B., Walczewska A., 2019. Docosahexaenoic Acid (DHA) Inhibits FADS2 Expression in Astrocytes but Increases Survival of Neurons Co-cultured with DHA-enriched Astrocytes. International Journal of Molecular and Cellular Medicine. 8(3),232-240. https://doi.org/10.22088/IJMCM.BUMS.8.3.232
8. Chandel N.S., 2021. Lipid metabolism. Cold Spring Harb Perspect Biol. 13, a040576
9. Fu Y., Zou T., Shen X., Nelson P.J., Li J., Wu C., Yang J., Zheng ., Bruns C., Zhao Y., Qin L., Dong Q., 2021. Lipid metabolism in cancer progression and therapeutic strategies. Medical Common. 2, 27–59. https://doi.org/10.1002/mco2.27
10. Cheng H., Wang M., Su J., Li Y., Long J., Chu J., Wan X., Cao Y., Li Q., 2022. Lipid Metabolism and Cancer. Life. 12. https://doi.org/10.3390/life12060784
11. McKee C.A., Lananna B.V., Musiek E.S., 2020. Circadian regulation of astrocyte function: implications for Alzheimer’s disease. Cellular and Molecular Life Sciences. 77, 1049–1058
12. Imierska M., Kurianiuk A., Błachnio-Zabielska A., 2020. The influence of physical activity on the bioactive lipids metabolism in obesity-induced muscle insulin resistance. Biomolecules. 10, 1665
13. Cao Y., Zhao L.W., Chen Z.X., Li S.H., 2024. New insights in lipid metabolism: Potential therapeutic targets for the treatment of Alzheimer’s disease. Frontier Neuroscience. 18,1430465
14. Khataminejad S., Mousavi-Sabet H., Sattari M., Vatandoust S., Eagderi S., 2013. A comparative study on body shape of the genus Alburnus (Rafinesque, 1820) in Iran, using geometric morphometric analysis. Caspian Journal of Environmental Sciences. 11(2), p.205.
15. Pashaee M., Shiravi A., Hojati V., 2016. The effect of hydroalcoholic extract of Berberis vulgaris on wound healing of diabetic wistar rats.Journal: Journal of Chemical Health Risks. 6(4), 319-325
16. Sizar O., Khare S., Patel P., Talati R .,2024. Statin medications. In: StatPearls [Internet]. StatPearls Publishing
17. Mira E., Mañes S., 2009. Immunomodulatory and anti-inflammatory activities of statins. Endocrine, Metabolic & Immune Disorder Targets. 9, 237–247
18. Medrano Sampayo L.E., Mengual G.D., 2023. Novel effects of statins on cancer via autophagy. Pharmaceuticals. 15(6), 648. https://doi.org/10.3390/ph15060648.
19. Greenwood J., Steinman L., Zamvil S.S., 2006. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nature Reviews Immunology. 6, 358–370
20. Roberts P.J., Mitin N., Keller P.J., Chenette E.J., Madigan J.P., Currin R.O., Cox A.D., Wilson O., Kirschmeier P., Der C.J., 2008. Rho Family GTPase modification and dependence on CAAX motif-signaled posttranslational modification. Journal of Biological Chemistry. 283(37), 25150-25163.
21. Wang C.Y., Liu P.Y., Liao J.K., 2008. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends in Molecular Medicine. 14(1), 37-44. https://doi.org/10.1016/j.molmed.2007.11.004
22. Razavi A.C., Mehta A., Sperling L.S., 2022. Statin therapy for the primary prevention of cardiovascular disease: Pros. Atherosclerosis. 356, 41–45
23. Bucci T., Menichelli D., Palumbo I.M., Pastori D., Ames P.R., Lip G.Y., Pignatelli P., 2025. Statins as an Adjunctive Antithrombotic Agent in Thrombotic Antiphospholipid Syndrome: Mechanisms and Clinical Implications. Cells. 14(5), 353. https://doi.org/10.3390/cells14050353
24. de Boer L.M., Oorthuys A.O., Wiegman A., Langendam M.W., Kroon J., Spijker R., Zwinderman A.H., Hutten B.A., 2022. Statin therapy and lipoprotein (a) levels: a systematic review and meta-analysis. European Journal of Preventive Cardiology. 29(5), 779-792.
25. Correale M., Abruzzese S., A Greco C., Di Biase M., D Brunetti N., 2014. Pleiotropic effects of statin in therapy in heart failure: a review. Current Vascular Pharmacology. 12(6), 873-884.
26. Zivkovic S., Maric G., Cvetinovic N., Lepojevic-Stefanovic D., Bozic Cvijan B., 2023. Anti-inflammatory effects of lipid-lowering drugs and supplements—a narrative review. Nutrients. 15(6),1517.
27. Koushki K., Shahbaz S.K., Mashayekhi K., Sadeghi M., Zayeri Z.D., Taba M.Y., Banach M., Al-Rasadi K., Johnston T.P., Sahebkar A., 2021. Anti-inflammatory action of statins in cardiovascular disease: the role of inflammasome and toll-like receptor pathways. Clinical Reviews in Allergy & Immunology. 60(2),175-199.
28. Şaman E., Cebova M., Barta A., Koneracka M., Zavisova V., Eckstein-Andicsova A., Danko M., Mosnacek J., Pechanova O., 2022. Combined therapy with simvastatin-and coenzyme-q10-loaded nanoparticles upregulates the Akt-eNOS pathway in experimental metabolic syndrome. International Journal of Molecular Sciences. 24(1), 276.
29. Gorabi A.M., Kiaie N., Hajighasemi S., Banach M., Penson P.E., Jamialahmadi T., Sahebkar A., 2019. Statin-induced nitric oxide signaling: mechanisms and therapeutic implications. Journal of Clinical Medicine. 8(12), 2051.
30. Pickett J.R., Wu Y., Zacchi L.F., Ta H.T., 2023. Targeting endothelial vascular cell adhesion molecule-1 in atherosclerosis: drug discovery and development of vascular cell adhesion molecule-1–directed novel therapeutics. Cardiovascular Research. 119(13), 2278-2293.https://doi.org/10.1093/cvr/cvad130
31. Scioli M.G., Storti G., D’Amico F., Rodríguez Guzmán R., Centofanti F., Doldo E., Céspedes Miranda E.M., Orlandi A., 2020. Oxidative stress and new pathogenetic mechanisms in endothelial dysfunction: potential diagnostic biomarkers and therapeutic targets. Journal of Clinical Medicine. 9(6), 1995. https://doi.org/10.3390/jcm9061995
32. Greenwood J., Mason J.C., 2007. Statins and the vascular endothelial inflammatory response. Trends Immunolgy. 28,88–98. https://doi.org/10.1016/j.it.2006.12.003
33. Nauryzbaevish A.S., Tatarinova G., Berikzhan O., Kunakbayev A., Tashenova G., Kapalbaevna A.G., Susarovnalbayeva K.M., Sholpan, S., 2023. Modulation of insulin secretion and lipid profiles through glutamate dehydrogenase activators in diabetic rabbits. Caspian Journal of Environmental Sciences. 21(5), 1229-1237. https://doi.org/10.22124/cjes.2023.7415
34. Satny M., Hubacek J.A., Vrablik M., 2021. Statins and inflammation. Current Atherosclerosis Reports. 23(12), 80.
35. Gendaszewska-Darmach E., Garstka M.A. and Błażewska K.M., 2021. Targeting small GTPases and their prenylation in diabetes mellitus. Journal of Medicinal Chemistry. 64(14), 9677-9710.
36. Gholamalizadeh H., Ensan B., Sukhorukov V.N., Sahebkar A., 2024. Targeting the CCL2–CCR2 signaling pathway: potential implications of statins beyond cardiovascular diseases. Journal of Pharmacy and Pharmacology. 76(2), 138-153.
37. Libby P., 2021. Targeting inflammatory pathways in cardiovascular disease: the inflammasome, interleukin-1, interleukin-6 and beyond. Cells. 10, 951
38. Monaco C., McNamara C.A., Slütter B., Foks A.C., Bekirano S., Mulder W.J., Gonçalves I., Lutgens E., LeDucq., 2025. Immunotherapy for atherosclerosis. Physiological Reviews. 105(4), 2141-2230. https://doi.org/10.1152/physrev.00016.2024
39. Markovic-Plese S., Singh A.K., Singh I., 2008. Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair. Future Neurology. 3(2),153-167. https://doi.org/ 10.2217/14796708.3.2.153
40. Bedeković D., Bošnjak I., Šarić S., Kirner D., Novak S., 2023. Role of inflammatory cytokines in rheumatoid arthritis and development of atherosclerosis: a review. Medicina. 59(9),1550. https://doi.org/ 10.3390/ medicina59091550
41. Sahebkar A., Rathouska J., Derosa G., Maffioli P., Nachtigal P., 2016. Statin impact on disease activity and C-reactive protein concentrations in systemic lupus erythematosus patients: a systematic review and meta-analysis of controlled trials. Autoimmunity Reviews. 15(4), 344-353. https://doi.org/10.1016/j.autrev. 2015.12.007
42. Zinellu A., Mangoni A.A., 2021. A systematic review and meta-analysis of the effect of statins on glutathione peroxidase, superoxide dismutase, and catalase. Antioxidants. 10(11),1841. https://doi.org/10. 3390/antiox10111841
43. Ray S., 2024. Role of statins in the management of dyslipidaemia. Indian Heart Journal. 76, S33-S37.https://doi.org/10.1016/j.ihj.2023.11.267
44. Johri N., Varshney S., Gandha S., Maurya A., Mittal P., Jangra S., Garg R., Saraf A., 2023. Association of cardiovascular risks in rheumatoid arthritis patients: Management, treatment and future perspectives. Health Sciences Review. 8, 100108.https://doi.org /https://doi.org/10.1016/j.hsr.2023.100108
45. Sheng X.I.A., Murphy M.J., MacDonald T.M., Wei L., 2012. Effectiveness of statins on total cholesterol and cardiovascular disease and all-cause mortality in osteoarthritis and rheumatoid arthritis. The Journal of Rheumatology. 39(1), 32-40.https://doi.org /10.3899/jrheum.110318
46. Soulaidopoulos S., Nikiphorou E., Dimitroulas T., Kitas G.D., 2018. The role of statins in disease modification and cardiovascular risk in rheumatoid arthritis. Frontiers in Medicine. 5, 24.https://doi.org/10.3389/fmed.2018.00024
47. Semalulu T., Tago A., Zhao K., Tselios K., 2023. Managing cardiovascular risk in systemic lupus erythematosus: considerations for the clinician. ImmunoTargets and Therapy. 175-186. https://doi.org/ 10.2147/ITT.S377076
48. Stojan G., Petri M., 2013. Atherosclerosis in systemic lupus erythematosus. Journal of Cardiovascular Pharmacology. 62(3), 255-262. https://doi.org /10.1097/FJC.0b013e31829dd857
49. Atzeni F., Rodríguez-Pintó I., Cervera R., 2024. Cardiovascular disease risk in systemic lupus erythematous: certainties and controversies. Autoimmunity Reviews. 23(10),103646. https://doi.org/10.1016/j.autrev.2024.103646
50. McGinley M.P., Goldschmidt C.H., Rae-Grant A.D., 2021. Diagnosis and treatment of multiple sclerosis: a review. Jama. 325(8),765-779.
51. von Haehling S., Anker S.D., Bassenge E., 2003. Statins and the role of nitric oxide in chronic heart failure. Heart Failure Reviews. 8(1), 99-106. https://doi.org/10.1023/a:1022103222857
52. Bhat A., Dalvi H., Jain H., Rangaraj N., Singh S.B., Srivastava S., 2021. Perspective insights of repurposing the pleiotropic efficacy of statins in neurodegenerative disorders: An expository appraisal. Current Research in Pharmacology and Drug Discovery. 2,100012. https://doi.org/https://doi.org/10.1016/j.crphar.2020.100012
53. Torrandell Haro G., Branigan G.L., Vitali F., Geifman N., Zissimopoulos J.M., Brinton R.D., 2020. Statin therapy and risk of Alzheimer's and age related neurodegenerative diseases. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 6(1), e12108.https://doi.org/10.1002/trc2.12108
54. Di Sarno A., Romano F., Arianna R., Serpico D., Lavorgna M., Savastano S., Colao A., Di Somma C., 2025. Lipid Metabolism and Statin Therapy in Neurodegenerative Diseases: An Endocrine View. Metabolites. 15(4), 282. https://doi.org /10.3390/metabo15040282
55. Liu C., Chen H., Hu B., Shi J., Chen Y., Huang K., 2023. New insights into the therapeutic potentials of statins in cancer. Frontiers in Pharmacology. 14, 1188926. https://doi.org/10.3389/fphar.2023.1188926
56. Zhang S., Ren X., Zhang B., Lan T., Liu B., 2024. A systematic review of statins for the treatment of nonalcoholic steatohepatitis: safety, efficacy, and mechanism of action. Molecules. 29(8),1859.
57. Jarr K.U., Nakamoto R., Doan B.H., Kojima Y., Weissman I.L., Advani R.H., Iagaru A., Leeper N.J., 2021. Effect of CD47 blockade on vascular inflammation. New England Journal of Medicine. 384(4), 382-383.
58. Mollazadeh H., Tavana E., Fanni G., Bo S., Banach M., Pirro M., Von Haehling S., Jamialahmadi T., Sahebkar A., 2021. Effects of statins on mitochondrial pathways. Journal of Cachexia, Sarcopenia and Muscle. 12(2), 237-251.
59. Alidadi M., Sahebkar A., Eslami S., Vakilian F., Jarahi L., Alinezhad-Namaghi M., Arabi S.M., Vakili S., Tohidinezhad, F., Nikooiyan Y., Norouzy A., 2021. The effect of curcumin supplementation on pulse wave velocity in patients with metabolic syndrome: a randomized, double-blind, placebo-controlled trial. In Pharmacological properties of plant-derived natural products and implications for human health (1-11). Cham: Springer International Publishing.
60. Bu D.X., Griffin G., Lichtman A.H., 2011. Mechanisms for the anti-inflammatory effects of statins. Current Opinion in Lipidology. 22(3),165-170.
61. Ridker P.M., Danielson E., Fonseca F.A., Genest J., Gotto Jr A.M., Kastelein J.J., Koenig W., Libby P., Lorenzatti A.J., MacFadyen J.G., Nordestgaard B.G., 2008. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New England Journal of Medicine. 359(21), 2195-2207.
62. Liao J.K., Laufs U., 2005. Pleiotropic effects of statins. Annu. Rev. Pharmacol. Toxicol. 45(1), 89-118.
63. Jain M.K., Ridker P.M., 2005. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nature Reviews Drug discovery. 4(12), 977-987.
64. Youssef S., Stüve O., Patarroyo J.C., Ruiz P.J., Radosevich J.L., Hur E.M., Bravo M., Mitchell D.J., Sobel R.A., Steinman L., Zamvil S.S., 2002. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 420(6911),78-84.
65. Kwak B.R., Mulhaupt F., Mach F., 2003. Atherosclerosis: anti-inflammatory and immunomodulatory activities of statins. Autoimmunity Reviews. 2(6), 332-338.