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 RisksPeyman 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
1 - Department of Vascular and Endovascular Surgery, Ayatollah taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran , Iran.
2 - Al-Aouadi College of Medicine, Al-Ayen Iraqi University, AUIQ, An Nasiriyah, Iraq.
3 - Department of Pediatrics, College of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran.
4 - Pedagogy and Psychology Department, Pedagogy Faculty, Urganch State University.
5 - Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
6 - Intern teacher of the "Pedagogy and Primary Education Methodology" department of Urgench Innovation University
7 - Department of Psychology and Medicine. Mamun university, Khiva, Uzbekistan
8 - Department of Medicine, Termez University of Economics and Service, Termez, Uzbekistan. norbek_xolboyev@tues.uz
9 - Department of biology , Ard.c., Islamic Azad university, Ardebil, Iran
10 - Department of Food Hygiene, University of Tehran, Tehran, Iran.
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 Mehrvarz S, Gholizadeh H. Floristic, life form and chorological studies of the Abshar protected area, Shirgah, Mazandaran Province, north of Iran. Casp. J. Environ. Sci. [Internet] 2017;15:165–80. Available from: https://cjes.guilan.ac.ir/article_2373.html
2. Sashindran Nair K. Alteration in the primary metabolites in three different tissues of silkworm, Bombyx mori L. under the influence of a Juvenoid, R394. Casp. J. Environ. Sci. [Internet] 2007;5:27–33. Available from: https://cjes.guilan.ac.ir/article_981.html
3. Roitman R, Schatton W, Ilyich Maevsky E. 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). Casp. J. Environ. Sci. [Internet] 2021;19:495–502. Available from: https://cjes.guilan.ac.ir/article_4935.html
4. Shojaeian A, Mehri-Ghahfarrokhi A, Banitalebi-Dehkordi M. 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. Int. J. Mol. Cell. Med. [Internet] 2020;9. Available from: http://ijmcmed.org/article-1-1379-en.html
5. Aghabozorg Afjeh SS, Ghaderian SMH, Mirfakhraie R, Piryaei M, Zaim Kohan H. Association Study of rs3184504 C>T Polymorphism in Patients With Coronary Artery Disease. Int. J. Mol. Cell. Med. [Internet] 2014;3. Available from: http://ijmcmed.org/article-1-145-en.html
6. Shojaee M, Golpasha MF, Maliji G, Bijani A, Mir SMA, Kani SNM. C-reactive protein levels in patients with periodontal disease and normal subjects. Int. J. Mol. Cell. Med. 2013;2:151.
7. Bewicz-Binkowska D, Zgórzyńska E, Dziedzic B, Walczewska A. Docosahexaenoic Acid (DHA) Inhibits FADS2 Expression in Astrocytes but Increases Survival of Neurons Co-cultured with DHA-enriched Astrocytes. Int. J. Mol. Cell. Med. [Internet] 2019;8. Available from: http://ijmcmed.org/article-1-1148-en.html
8. Chandel NS. Lipid metabolism. Cold Spring Harb. Perspect. Biol. 2021;13:a040576.
9. Fu Y, Zou T, Shen X, Nelson PJ, Li J, Wu C, et al. Lipid metabolism in cancer progression and therapeutic strategies. MedComm 2021;2:27–59.
10. Cheng H, Wang M, Su J, Li Y, Long J, Chu J, et al. Lipid Metabolism and Cancer. Life [Internet] 2022;12. Available from: https://www.mdpi.com/2075-1729/12/6/784
11. McKee CA, Lananna B V, Musiek ES. Circadian regulation of astrocyte function: implications for Alzheimer’s disease. Cell. Mol. Life Sci. 2020;77:1049–58.
12. Imierska M, Kurianiuk A, Błachnio-Zabielska A. The influence of physical activity on the bioactive lipids metabolism in obesity-induced muscle insulin resistance. Biomolecules 2020;10:1665.
13. Cao Y, Zhao LW, Chen ZX, Li SH. New insights in lipid metabolism: Potential therapeutic targets for the treatment of Alzheimer’s disease. Front. Neurosci. 2024;18:1430465.
14. A Comparative Study on Body Shape of the Genus Alburnus (Rafinesque, 1820) in Iran, Using Geometric Morphometric Analysis. Casp. J. Environ. Sci. [Internet] 2013;11:205–15. Available from: https://cjes.guilan.ac.ir/article_1126.html
15. Pashaee M, Shiravi A, Hojati V. The effect of hydroalcoholic extract of Berberis vulgaris on wound healing of diabetic wistar rats. 2016;
16. Sizar O, Khare S, Patel P, Talati R. Statin medications. In: StatPearls [Internet]. StatPearls Publishing; 2024.
17. Mira E, Mañes S. Immunomodulatory and anti-inflammatory activities of statins. Endocrine, Metab. Immune Disord. Targets (Formerly Curr. Drug Targets-Immune, Endocr. Metab. Disord. 2009;9:237–47.
18. Medrano Sampayo LE, Mengual Guevara D. Novel effects of statins on cancer via autophagy. 2023;
19. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat. Rev. Immunol. 2006;6:358–70.
20. Roberts PJ, Mitin N, Keller PJ, Chenette EJ, Madigan JP, Currin RO, et al. Rho Family GTPase modification and dependence on CAAX motif-signaled posttranslational modification. J. Biol. Chem. 2008;283:25150–63.
21. Wang CY, Liu PY, Liao JK. Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol. Med. 2008;14:37–44.
22. Razavi AC, Mehta A, Sperling LS. Statin therapy for the primary prevention of cardiovascular disease: Pros. Atherosclerosis 2022;356:41–5.
23. Bucci T, Menichelli D, Palumbo IM, Pastori D, Ames PRJ, Lip GYH, et al. Statins as an Adjunctive Antithrombotic Agent in Thrombotic Antiphospholipid Syndrome: Mechanisms and Clinical Implications. Cells [Internet] 2025;14. Available from: https://www.mdpi.com/2073-4409/14/5/353
24. de Boer LM, Oorthuys AOJ, Wiegman A, Langendam MW, Kroon J, Spijker R, et al. Statin therapy and lipoprotein (a) levels: a systematic review and meta-analysis. Eur. J. Prev. Cardiol. 2022;29:779–92.
25. Correale M, Abruzzese S, A Greco C, Di Biase M, D Brunetti N. Pleiotropic effects of statin in therapy in heart failure: a review. Curr. Vasc. Pharmacol. 2014;12:873–84.
26. Zivkovic S, Maric G, Cvetinovic N, Lepojevic-Stefanovic D, Bozic Cvijan B. Anti-inflammatory effects of lipid-lowering drugs and supplements—A narrative review. Nutrients 2023;15:1517.
27. Koushki K, Shahbaz SK, Mashayekhi K, Sadeghi M, Zayeri ZD, Taba MY, et al. Anti-inflammatory Action of Statins in Cardiovascular Disease: the Role of Inflammasome and Toll-Like Receptor Pathways. Clin. Rev. Allergy Immunol. 2021;60:175–99.
28. Şaman E, Cebova M, Barta A, Koneracka M, Zavisova V, Eckstein-Andicsova A, et al. Combined therapy with simvastatin-and coenzyme-q10-loaded nanoparticles upregulates the Akt-eNOS pathway in experimental metabolic syndrome. Int. J. Mol. Sci. 2022;24:276.
29. Gorabi AM, Kiaie N, Hajighasemi S, Banach M, Penson PE, Jamialahmadi T, et al. Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications. J. Clin. Med. [Internet] 2019;8. Available from: https://www.mdpi.com/2077-0383/8/12/2051
30. Pickett JR, Wu Y, Zacchi LF, Ta HT. Targeting endothelial vascular cell adhesion molecule-1 in atherosclerosis: drug discovery and development of vascular cell adhesion molecule-1-directed novel therapeutics. Cardiovasc. Res. 2023;119:2278–93.
31. Scioli MG, Storti G, D’Amico F, Rodríguez Guzmán R, Centofanti F, Doldo E, et al. Oxidative Stress and New Pathogenetic Mechanisms in Endothelial Dysfunction: Potential Diagnostic Biomarkers and Therapeutic Targets. J. Clin. Med. 2020;9.
32. Greenwood J, Mason JC. Statins and the vascular endothelial inflammatory response. Trends Immunol. 2007;28:88–98.
33. Nauryzbaevish AS, Tatarinova G, Berikzhan O, Kunakbayev4 A, Tashenova G, Kapalbaevna AG, et al. Modulation of insulin secretion and lipid profiles through glutamate dehydrogenase activators in diabetic rabbits. Casp. J. Environ. Sci. [Internet] 2023;21:1229–37. Available from: https://cjes.guilan.ac.ir/article_7415.html
34. Satny M, Hubacek JA, Vrablik M. Statins and inflammation. Curr. Atheroscler. Rep. 2021;23:1–8.
35. Gendaszewska-Darmach E, Garstka MA, Błażewska KM. Targeting small GTPases and their prenylation in diabetes mellitus. J. Med. Chem. 2021;64:9677–710.
36. Gholamalizadeh H, Ensan B, Sukhorukov VN, Sahebkar A. Targeting the CCL2–CCR2 signaling pathway: potential implications of statins beyond cardiovascular diseases. J. Pharm. Pharmacol. 2024;76:138–53.
37. Libby P. Targeting inflammatory pathways in cardiovascular disease: the inflammasome, interleukin-1, interleukin-6 and beyond. Cells 2021;10:951.
38. Monaco C, McNamara CA, Slütter B, Foks AC, Bekiranov S, Mulder WJM, et al. Immunotherapy for atherosclerosis. Physiol. Rev. 2025;
39. Markovic-Plese S, Singh AK, Singh I. Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair. Future Neurol. 2008;3:153.
40. Bedeković D, Bošnjak I, Šarić S, Kirner D, Novak S. Role of Inflammatory Cytokines in Rheumatoid Arthritis and Development of Atherosclerosis: A Review. Medicina (Kaunas). 2023;59.
41. Sahebkar A, Rathouska J, Derosa G, Maffioli P, Nachtigal P. Statin impact on disease activity and C-reactive protein concentrations in systemic lupus erythematosus patients: A systematic review and meta-analysis of controlled trials. Autoimmun. Rev. 2015;15.
42. Zinellu A, Mangoni AA. A Systematic Review and Meta-Analysis of the Effect of Statins on Glutathione Peroxidase, Superoxide Dismutase, and Catalase. Antioxidants (Basel, Switzerland) 2021;10.
43. Ray S. Role of statins in the management of dyslipidaemia. Indian Heart J. 2024;76 Suppl 1:S33–7.
44. Johri N, Varshney S, Gandha S, Maurya A, Mittal P, Jangra S, et al. Association of cardiovascular risks in rheumatoid arthritis patients: Management, treatment and future perspectives. Heal. Sci. Rev. [Internet] 2023;8:100108. Available from: https://www.sciencedirect.com/science/article/pii/S277263202300034X
45. Sheng X, Murphy MJ, Macdonald TM, Wei L. Effectiveness of statins on total cholesterol and cardiovascular disease and all-cause mortality in osteoarthritis and rheumatoid arthritis. J. Rheumatol. 2012;39:32–40.
46. Soulaidopoulos S, Nikiphorou E, Dimitroulas T, Kitas GD. The Role of Statins in Disease Modification and Cardiovascular Risk in Rheumatoid Arthritis. Front. Med. 2018;5:24.
47. Semalulu T, Tago A, Zhao K, Tselios K. Managing Cardiovascular Risk in Systemic Lupus Erythematosus: Considerations for the Clinician. ImmunoTargets Ther. 2023;12:175–86.
48. Stojan G, Petri M. Atherosclerosis in systemic lupus erythematosus. J. Cardiovasc. Pharmacol. 2013;62:255–62.
49. Atzeni F, Rodríguez-Pintó I, Cervera R. Cardiovascular disease risk in systemic lupus erythematous: Certainties and controversies. Autoimmun. Rev. [Internet] 2024;23:103646. Available from: https://www.sciencedirect.com/science/article/pii/S156899722400137X
50. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: a review. Jama 2021;325:765–79.
51. von Haehling S, Anker SD, Bassenge E. Statins and the role of nitric oxide in chronic heart failure. Heart Fail. Rev. 2003;8:99–106.
52. Bhat A, Dalvi H, Jain H, Rangaraj N, Singh SB, Srivastava S. Perspective insights of repurposing the pleiotropic efficacy of statins in neurodegenerative disorders: An expository appraisal. Curr. Res. Pharmacol. Drug Discov. [Internet] 2021;2:100012. Available from: https://www.sciencedirect.com/science/article/pii/S2590257120300146
53. Torrandell-Haro G, Branigan GL, Vitali F, Geifman N, Zissimopoulos JM, Brinton RD. Statin therapy and risk of Alzheimer’s and age-related neurodegenerative diseases. Alzheimer’s Dement. (New York, N. Y.) 2020;6:e12108.
54. Di Sarno A, Romano F, Arianna R, Serpico D, Lavorgna M, Savastano S, et al. Lipid Metabolism and Statin Therapy in Neurodegenerative Diseases: An Endocrine View. Metabolites [Internet] 2025;15. Available from: https://www.mdpi.com/2218-1989/15/4/282
55. Liu C, Chen H, Hu B, Shi J, Chen Y, Huang K. New insights into the therapeutic potentials of statins in cancer. Front. Pharmacol. 2023;14:1188926.
ORIGINAL ARTICLE
Statins beyond Lipid Lowering: A Narrative Review of Their Pleiotropic Anti-inflammatory Mechanisms through Lipid Metabolism, Immune Modulation, and Cell Signaling
Peyman Bakhshaei Shahrebabaki 1, Raed Fanoukh Aboqader2, Alizamen Salehifard Jouneghani3, Mukhayya Khusinovna Djumaniyazova4, Alireza Salehifard Jouneghani5, Yuldoshev Jushkinbek Erkaboy ugli6 ,Umida Sadikova7 , Norbek Kholboyev 8, Farnaz Farzaneh Dehkordi 9*,Farhad Safarpoor Dehkordi10
1Department of Vascular and Endovascular Surgery, Ayatollah taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran , Iran.
2Al-Aouadi College of Medicine,Al-Ayen Iraqi University, AUIQ, An Nasiriyah ,Iraq
3Department of Pediatrics, College of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran.
4Pedagogy and Psychology Department, Pedagogy Faculty, Urganch State University.
5Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia,
6 Intern teacher of the "Pedagogy and Primary Education Methodology" department of Urgench Innovation University
7 Department of Psychology and Medicine. Mamun University, Khiva, Uzbekistan,
8Department of Medicine, Termez University of Economics and Service, Termez, Uzbekistan.
9Department of biology , Ard.c., Islamic Azad university, Ardebil, Iran
10Department of Food Hygiene, University of Tehran, Tehran, Iran.
*Corresponding author: FarnazFarzaneh@iau.ac.ir DOI: 10.60833/jchr.2025.1207878
|
KEYWORDS Statins, lipid metabolism inflammatory diseases autoimmune, | 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’ |
INTRODUCTION
Statins are commonly used to manage high cholesterol and help prevent heart disease. They work by blocking an enzyme your body needs to make cholesterol, especially lowering the bad kind called LDL cholesterol[1]. There’s solid evidence that statins can decrease the chances of heart events like heart attacks and strokes, mainly by reducing cholesterol levels. Statins demonstrate multifaceted anti-inflammatory effects by influencing immune responses, modifying the movement of leukocytes, and changing cellular signaling pathways. They affect lipid metabolism, boost nitric oxide synthesis, and control adhesion molecules, which leads to diminished inflammation and supports vascular integrity in different circumstances[2,3].
Although statins offer notable anti-inflammatory effects, some research indicates possible adverse effects, including myopathy and changes in inflammation status due to cholesterol reduction, highlighting the necessity for careful evaluation in clinical settings.
Studies have shown that statins might do more than just lower cholesterol. They appear to have anti-inflammatory properties, meaning they can help reduce inflammation. Research, including observational studies and clinical trials, indicates that statins can lower inflammation markers, stabilize plaque in arteries, and affect immune system responses, even when cholesterol levels don’t change[4]. For example, the JUPITER trial found that people with high blood marker levels called hs-CRP but normal LDL cholesterol still benefited from statins, pointing to their potential anti-inflammatory effects. Some evidence suggests that statins may help with various inflammatory and autoimmune diseases like rheumatoid arthritis and multiple sclerosis[5,6].
This article will examine how statins may help reduce inflammation, alter specific cellular processes, and their potential roles in diseases beyond cholesterol management.
Lipid metabolism
Lipid metabolism encompasses the creation and breakdown of primary lipid types, such as fatty acids, triacylglycerols, phospholipids, and isoprenoids regulated by acetyl-CoA[7]. It also involves cholesterol metabolism, an essential factor in cardiovascular disease, and the production of ketone bodies. In insects, lipid metabolism plays a vital role in development, reproduction, and other functions, mainly in the fat body. This process includes lipogenic and lipolytic enzymes, hormones, and transcription factors, making it a key focus for pest control methods. It is also a complex mechanism crucial for sustaining physiological functions. Disruptions in lipid metabolism can result in several diseases, including intervertebral disc degeneration (IDD), by facilitating the breakdown of the extracellular matrix, promoting cell death, and causing inflammation, ultimately contributing to IDD's development[8].
Lipid metabolism involves lipid biosynthesis and degradation, including fatty acid metabolism, triglyceride metabolism, and cholesterol metabolism. Key pathways include WNT-b-catenin and HIF12, regulating lipid synthesis, storage, and apoptosis, significantly impacting tumor growth and progression[9].
It involves multiple signaling pathways that generate bioactive lipid molecules, such as fatty acids and eicosanoids. These regulate cellular processes including growth, apoptosis, inflammation, and chemotherapy, ultimately influencing cancer therapy and drug resistance[10].
Functions of Lipid Metabolism
Energy Reserves: Lipids are efficient energy stores vital for cellular activities and survival [11].
Membrane Integrity: Lipids are essential elements of cell membranes, playing a key role in maintaining membrane fluidity and stability [11,12].
Signaling Agents: Different lipids are signaling agents, affecting inflammation and programmed cell death[11].
Lipid Metabolism and Cancer
Tumor Development: Changes in lipid metabolism are characteristic of cancer, facilitating tumor development and spread through increased fat uptake and storage.[10]
Statins
Statins, or HMG-CoA reductase inhibitors, are primarily known for their cholesterol-lowering effects, significantly impacting cardiovascular disease management. They reduce total cholesterol and LDL levels and exhibit pleiotropic effects that contribute to cardiovascular protection beyond lipid regulation[14]. This multifaceted action includes improving endothelial function, reducing inflammation, and stabilizing atherosclerotic plaques, collectively lowering morbidity and mortality rates associated with atherosclerotic cardiovascular disease (ASCVD)[15]. Statins are cholesterol-lowering drugs that act as enzyme inhibitors, crucial in managing coronary heart disease. Notable examples include atorvastatin and simvastatin, which generated significant revenues in 2002, highlighting their dominance in the pharmaceutical market for cholesterol-lowering medications[16].
Statins work by inhibiting HMG-CoA reductase, which decreases cholesterol production and increases LDL receptor expression, reducing circulating LDL levels. They also influence the metabolism of isoprenoid intermediates, essential for activating signaling proteins like Ras and Rho, involved in multiple cellular functions. Statins display immunomodulatory properties by affecting the differentiation and functionality of immune cells, subsequently lowering inflammation. They reduce the levels of inflammatory cytokines and improve endothelial function, contributing to vascular health[17,18].
Statins interfere with the prenylation of small GTPases, impacting cell growth and inflammatory responses. They also boost nitric oxide synthase activity while inhibiting the expression of adhesion molecules, which enhances their anti-inflammatory properties[19].
Inhibition of Isoprenoid Synthesis and GTPase Signaling
disorders. Gaining insights into these mechanisms could inform therapeutic approaches.hypochlorite solution for 10 minutes, washed three times with tap water and soaked in distilled water overnight. A planting substrate containing virgin soil(loamy)-sand
(1:2 w/w) was used for planting pistachio seeds. Mineral sulfur (Table 1) treatments at three concentrations of 2%, 4% and 8% (w/w) were applied before and after inoculation with
V. dahliae. Statins inhibit the HMG-CoA reductase enzyme, decreasing not only cholesterol synthesis but also the production of isoprenoid intermediates, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These molecules are necessary for the prenylation of small GTPases (e.g., Rho, Rac, Ras), which are involved in intracellular signaling cascades that regulate inflammation[20]. By disrupting GTPase function, statins suppress the NF-κB signaling pathway, a key regulator of inflammatory gene transcription. This leads to reduced expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6[15,21].
Statins have various additional effects, including anti-inflammatory, antioxidative, antithrombotic, immunomodulatory, and vascular protective. These additional effects are primarily ascribed to inhibiting FPP and GPP prenylation, which disrupts small GTPases (Ras, Rho, Rac) and related signaling pathways that control inflammation, hypertrophy, and the production of reactive oxygen species (ROS)[19,22]. Statins are currently being investigated for a range of therapeutic applications beyond treating dyslipidemia, such as in the management of autoimmune diseases, cancer, sepsis, preeclampsia, and heart failure. Notably, in cases of heart failure, whether ischaemic or non-ischaemic, statins may alleviate adverse cardiac remodeling by influencing the behavior of cardiomyocytes and fibroblasts, regardless of cholesterol levels[23,24].
Though observational and experimental studies, such as those by Correale et al., indicate that lipophilic statins (like atorvastatin) can enhance ventricular function and lower the risk of cardiac death, randomized controlled trials (RCTs) involving hydrophilic statins (such as rosuvastatin in CORONA and GISSI-HF) did not demonstrate significant improvements in outcomes. This inconsistency may be due to the limited tissue penetration of hydrophilic statins, which hinders their pleiotropic effects within the myocardium. Despite the encouraging findings, statins may also pose certain risks, including mitochondrial myopathy, depletion of selenoproteins, and pro-inflammatory reactions that can arise from excessive reductions in cholesterol. Therefore, additional randomized trials comparing the effects of lipophilic and hydrophilic statins are warranted[25].
|
Figure 1: Schematic figure on statins and the reduction of inflammatory pathways.
Enhancement of Endothelial Function
A key mechanism through which statins exert anti-inflammatory effects is improving endothelial function, a critical factor in maintaining vascular homeostasis and preventing atherogenesis. Endothelial cells line the inner surface of blood vessels and regulate vascular tone, leukocyte adhesion, thrombosis, and barrier integrity. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability and increased oxidative stress, is an early hallmark of cardiovascular disease and systemic inflammation[26,27].
Upregulation of eNOS and Increased NO Production.
Statins promote the expression and activity of endothelial nitric oxide synthase (eNOS), the enzyme responsible for NO production in endothelial cells. They do this through multiple mechanisms[28]:
· Inhibition of RhoA and upregulation of eNOS mRNA: By inhibiting isoprenoid synthesis and preventing the activation of the small GTPase RhoA, statins promote eNOS expression.
· Activation of PI3K/Akt pathway: Statins enhance Akt-mediated phosphorylation of eNOS, increasing its enzymatic activity.
· Prevention of eNOS uncoupling: Statins help maintain eNOS in its functional dimeric form, preserving NO synthesis[29].
The resulting increase in NO production has several protective effects, such as vasodilation and improved blood flow, inhibition of platelet aggregation, suppression of vascular smooth muscle cell proliferation, and reduction of leukocyte adhesion and transmigration[23,29].
Reduction of Endothelial Adhesion Molecules
Inflammation induces the expression of adhesion molecules such as VCAM-1, ICAM-1, and E-selectin on endothelial cells, promoting leukocyte adhesion and migration into the vascular wall. Statins inhibit the expression of these molecules by suppressing NF-κB signaling, thereby attenuating the initial steps of vascular inflammation[30].
Antioxidant Effects on the Endothelium
Oxidative stress impairs NO signaling by converting NO to peroxynitrite and promoting endothelial dysfunction. Statins reduce reactive oxygen species (ROS) production by inhibiting NADPH oxidase, increase antioxidant enzyme levels, such as superoxide dismutase (SOD) and preserve NO bioavailability by reducing oxidative degradation[31].
Inhibition of Endothelial Apoptosis
Statins have been shown to protect endothelial cells from apoptosis triggered by oxidized LDL, inflammatory cytokines, or disturbed flow. This cytoprotective effect supports vascular integrity and reduces endothelial activation[32].
Inhibition of Cytokine Production
Statins have been shown to significantly reduce the expression of several pro-inflammatory cytokines, including: Tumor necrosis factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6)[34].
These cytokines activate endothelial cells, recruit leukocytes, and amplify the inflammatory cascade. The suppression of cytokine expression by statins occurs through multiple mechanisms: Inhibition of NF-κB activation: Statins interfere with the NF-κB signaling pathway by preventing the prenylation of small GTP-binding proteins (e.g., Rho, Rac). NF-κB is a transcription factor central to the induction of cytokine genes[35].
|
Figure 2: Statins' anti-inflammatory mechanism by upregulating NOS, antioxidant effect, reducing adhesion molecules, and reducing apoptosis |
Reduced MAPK pathway signaling: Statins also blunt the mitogen-activated protein kinase (MAPK) pathway, contributing to cytokine gene transcription under inflammatory conditions[27] .These effects have been demonstrated in various cell types, including monocytes, macrophages, endothelial cells, and vascular smooth muscle cells.
Downregulation of Chemokine Production
Statins also suppress the synthesis of key chemokines, particularly: Monocyte chemoattractant protein-1 (MCP-1/CCL2), IL-8 (CXCL8), and RANTES (CCL5)[36].
These chemokines attract monocytes, neutrophils, and other leukocytes to sites of inflammation, such as atherosclerotic plaques or inflamed tissues. By decreasing chemokine expression, statins limit immune cell infiltration, stabilize plaque, and reduce tissue injury.
Effects in Clinical and Experimental Models
Numerous in vitro studies, animal models, and clinical trials have validated the anti-cytokine effects of statins. In patients with coronary artery disease, statin therapy is associated with reduced serum levels of IL-6 and CRP, independent of lipid lowering. In murine models of arthritis and colitis, statins have shown efficacy in reducing cytokine-driven inflammation[26].
In sepsis and acute respiratory distress syndrome (ARDS) models, statins reduce TNF-α and IL-1β levels and improve outcomes, supporting their systemic immunomodulatory roles. Statins strongly inhibit pro-inflammatory cytokines and chemokines by modulating intracellular signaling pathways such as NF-κB and MAPKs. This suppression limits leukocyte activation and recruitment, reduces tissue inflammation, and contributes to statin therapy's broader anti-inflammatory and plaque-stabilizing effects[36,37].
Figure 3: Anti-inflammatory effects of Statins by modulation the cytokines.
Immunomodulatory Effects
Statins impact both innate and adaptive immunity. They reduce major histocompatibility complex class II (MHC-II) expression and co-stimulatory molecules (CD80/CD86) on antigen-presenting cells, thereby attenuating T-cell activation[38]. Furthermore, statins:
• Shift T-helper cell responses from Th1/Th17 toward a regulatory T cell (Treg) phenotype
• Inhibit dendritic cell maturation
• Suppress autoimmune reactivity
These immunomodulatory properties have implications for treating multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
Multiple sclerosis is characterized by immune-mediated demyelination in the central nervous system. Statins can shift T-helper cell responses from a pro-inflammatory Th1 phenotype towards an anti-inflammatory Th2 phenotype, potentially reducing neuroinflammation. Some clinical trials have explored the use of statins as adjunct therapy in MS, with varying outcomes. For instance, a study evaluating rosuvastatin therapy observed changes in gene expression related to immune regulation, suggesting potential benefits[39].
Rheumatoid arthritis involves chronic inflammation of the joints, driven by autoimmune mechanisms. Statins have been shown to reduce levels of pro-inflammatory cytokines such as TNF-α and IL-6, which are central to RA pathogenesis. A meta-analysis indicated that statins are safe in RA patients and may reduce disease activity. Additionally, statin therapy has been associated with a lower risk of major adverse cardiovascular events in this population[40].
SLE is a systemic autoimmune disease with diverse clinical manifestations. Statins can modulate immune responses by affecting antigen presentation and cytokine production. While some studies suggest that statins may reduce disease activity in SLE, the evidence remains inconclusive. A meta-analysis did not find definitive proof that statins effectively control SLE, highlighting the need for further research[41].
Antioxidant Effects
Statins notably raised the levels of the antioxidant enzymes GPx and SOD in the bloodstream, but did not affect catalase levels, among patients with different cardiovascular risk factors. Statins limit oxidative stress by reducing reactive oxygen species (ROS) production and inhibiting NADPH oxidase. This contributes to their ability to stabilize atherosclerotic plaques and prevent endothelial dysfunction, further reinforcing their anti-inflammatory action. In 15 studies involving 17 treatment groups with a total of 773 participants (average age 53 years, 54% male), treatment with statins notably elevates the levels of antioxidant enzymes GPx and SOD in various biological samples, indicating the protective benefits of these medications against oxidative stress. Further intervention studies are needed to explore the antioxidant properties of statins as crucial factors in their beneficial roles for both primary and secondary cardiovascular prevention, to identify the ideal biological matrix for assessing GPx and SOD, and to pinpoint specific patient populations that may greatly benefit from the combined antioxidant and cholesterol-lowering effects of this drug class[42].
Clinical Implications and Emerging Applications
While statins are prescribed primarily for dyslipidemia, a substantial portion of their cardiovascular benefits is now attributed to plaque stabilization, endothelial protection, and reduction of systemic inflammation. These effects reduce the incidence of acute coronary syndromes and stroke, even in patients with normal LDL-C but elevated high-sensitivity C-reactive protein (hs-CRP), as shown in the JUPITER trial[43].
Autoimmune and Inflammatory Disorders
As discussed in previous sections, statins have shown therapeutic potential as adjunct agents in diseases such as:
Rheumatoid arthritis (RA)
Individuals with rheumatoid arthritis (RA) face a 1.5 to 2.0 times higher risk of developing coronary artery disease (CAD) compared to the general population, a risk level comparable to that associated with diabetes mellitus. Furthermore, those with RA are twice as likely to experience heart failure. This heightened risk is even more significant in RA patients who test positive for rheumatoid factor than in those who are seronegative. Typically, patients with RA exhibit fewer classic signs and symptoms of heart failure, often receive less aggressive treatment, and experience poorer health outcomes. Additionally, RA patients tend to have decreased muscle mass and a low body mass index, which may result from ongoing inflammation, reduced physical activity, or a combination [44].
Low body weight in individuals with RA seems to correlate with a worse prognosis. In a study involving 430 patients with rheumatoid arthritis (181 exposed to statins and 249 not exposed), statins led to a 16% reduction in total cholesterol (TC) levels and were linked to a significant decrease in cardiovascular disease (CVD) risk (adjusted hazard ratio (HR) 0.45, 95% confidence interval) and all-cause mortality[45]. Similar findings were observed in a smaller cohort of 78 RA patients, where statin intervention resulted in a 15% reduction in TC levels for secondary prevention. Nevertheless, in this group, statins did not provide significant protection against CVD and all-cause mortality. The role of statins in enhancing clinical features of rheumatoid arthritis (RA) may be related to their ability to influence various stages of the disease's development. Persistent joint inflammation is caused by excessive production of various inflammatory substances, such as cytokines, growth factors, adhesion molecules, and T lymphocytes. Considering that TNF-α and interleukins play crucial roles in the chronic arthritis process, they are essential factors to consider[46].
Systemic lupus erythematosus (SLE)
SLE poses a comparable risk for cardiovascular disease as type 1 diabetes, making it an independent predictor of cardiovascular events (CVE). The prevalence of cardiovascular disease among SLE patients has been estimated to range from 6% to 16%, with one extensive population study revealing that 25.6% of hospitalized SLE patients had atherosclerotic CVD[47]. The rapid progression of atherosclerosis in SLE has been linked to the higher occurrence of conventional risk factors, such as hypertension and dyslipidemia, along with disease-specific risk factors and harmful effects from medications used in its treatment. Endothelial dysfunction is thought to be the initial step in the pathophysiological chain, as evidenced by the upregulated expression of adhesion molecules including ICAM-1 (intercellular adhesion molecule-1), VCAM (vascular adhesion molecule-1), VEGF (vascular endothelial growth factor), pentraxin-3, thrombomodulin, IP-10 (interferon-γ-induced protein 10), and MCP-1 (monocyte chemoattractant protein-1)[47,48].
A significant factor contributing to cardiovascular disease (CVD) in systemic lupus erythematosus (SLE) is early onset atherosclerosis. Several elements play a role in this issue. Firstly, inflammation promotes the development of atherosclerosis. Additionally, treatments designed to reduce inflammation, such as corticosteroids and disease-modifying antirheumatic drugs, may have adverse cardiovascular effects. Furthermore, SLE patients often experience higher rates of traditional cardiovascular risk factors, including smoking, hypertension, and obesity. There are multiple treatment approaches to mitigate CVD-related complications in SLE. The foundational strategy involves managing overall inflammation with anti-inflammatory medications, which can help alleviate the atherosclerosis driven by inflammation. Another crucial approach is addressing dyslipidemia with statins. In addition to lowering cholesterol production within cells, statins provide various benefits, such as preventing thrombosis and endothelial dysfunction, stabilizing plaques, and modulating the immune system[49].
Multiple sclerosis (MS)
Multiple sclerosis (MS) is a disease characterized by inflammation and damage to the myelin in the central nervous system (CNS), commonly leading to disability in younger individuals. Approximately 2.5 million people worldwide are affected, with a lifetime risk estimated at one in 400. The onset of this condition typically occurs between the ages of 20 and 50, and it is more prevalent in females than males. Research has shown that statins may help mitigate and even reverse the progression of experimental autoimmune encephalomyelitis (EAE), which serves as a mouse model for MS. Statins could provide protective benefits through various mechanisms relevant to MS[50].
Statins might exhibit anti-inflammatory effects by promoting the downregulation of pro-inflammatory Th1 cytokines from T cells, increasing the release of anti-inflammatory Th2 cytokines, encouraging the transition of Th1 cells to Th2 cells, and facilitating the differentiation of Th0 cells into Th2 cells[27].
Statins can reduce the activity of inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) that can have harmful effects in the CNS. Additionally, statins have neuroprotective properties and can enhance remyelination within the CNS. Integrating statins into treatment regimens for autoimmune diseases may improve outcomes when combined with immunosuppressants or biologics, especially in patients at elevated cardiovascular risk[51,52].
Infectious Diseases and Sepsis
Given their endothelial-protective and anti-inflammatory effects, statins have been studied in acute infections, including:
Sepsis and acute respiratory distress syndrome (ARDS):
Acute respiratory distress syndrome (ARDS) is a serious condition marked by widespread damage to the alveoli caused by inflammation, damage to the endothelium, and lung remodeling that follows an initial injury (1). In the United States, it is estimated that there are over 150,000 cases and more than 70,000 deaths from ARDS annually (2). Despite decades of research, there remains no effective pharmacologic treatment for ARDS (3). Statins have anti-inflammatory effects in addition to their ability to lower lipid levels (5). Consequently, there is significant interest in using statins not only as a treatment for inflammatory diseases such as septic shock and ARDS but also to prevent inflammatory complications such as ARDS following an injury (6). Initial findings from animal studies of lung injury support these strategies (7–9), and observational studies have indicated better outcomes for patients who took statins before developing pneumonia, sepsis, and other inflammatory or infectious diseases (10–13). Nevertheless, evidence demonstrating improved outcomes in human lung injury cases is insufficient, and a recent study by Kor et al indicated no advantages in outcomes for patients with acute lung injury or ARDS who were administered statins before hospitalization.COVID-19: Retrospective data suggest that statin use may be associated with reduced mortality and improved outcomes in hospitalized patients, likely due to anti-inflammatory and endothelial-stabilizing effects.
Neurodegenerative Disorders
Inflammation plays a critical role in the pathogenesis of Alzheimer’s disease and other neurodegenerative conditions. Statins, which can cross the blood-brain barrier—especially the lipophilic ones—are being evaluated for their potential to reduce neuroinflammation and delay cognitive decline. However, the findings are not yet definitive. In a study involving 288,515 participants, 144,214 patients received statin therapies, while 144,301 did not undergo statin treatment. The average duration of follow-up was 5.1 years with a standard deviation of 2.3 years. The use of statins was associated with a decreased occurrence of Alzheimer's disease, dementia, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis[53]. For all neurodegenerative diseases (NDD), the incidence was lower for all statins except fluvastatin, indicating variations based on individual risk profiles. Pathway analysis revealed distinct and shared profiles related to the effectiveness of risk reduction. In the discussion, it is emphasized that both the advantages and disadvantages of statins regarding neurological outcomes must be considered when prescribing them to populations at risk for NDD. The common pathways activated by statins underscore essential systems necessary for reducing risk, while the unique targets present opportunities for advancing a tailored medical approach to preventing neurodegenerative diseases[53].
So, statins can potentially influence microglial activation, reducing proinflammatory substances contributing to neurodegeneration. Scientists have discovered that they can decrease the production of amyloid-beta, a key component in the pathology of Alzheimer's disease. Statins also affect apolipoprotein E (ApoE) levels, which are crucial for synaptic function and may influence neurodegenerative processes[54].
Cancer
Emerging data suggest that statins may influence tumor microenvironments, reduce cancer cell proliferation, and modulate immune responses, particularly in inflammation-associated malignancies (e.g., colorectal, prostate, breast cancers). Clinical trials are ongoing to evaluate statins as adjuvant therapies in oncology.
The expanding knowledge of statins’ anti-inflammatory and immunomodulatory mechanisms supports their repurposing in diverse clinical settings. While robust evidence supports their benefits in cardiovascular and autoimmune diseases, further randomized controlled trials are needed to establish their efficacy and safety in infectious diseases, neurodegenerative disorders, and oncology. Statins may thus represent a cost-effective adjunct strategy in managing complex, inflammation-driven diseases[55].
Table 1. Summary of Key Studies on Anti-inflammatory and Pleiotropic Effects of Statins[56–65]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CONCLUSIONS
Anti-inflammatory and Immune Modulating Effects: Statins exhibit significant anti-inflammatory properties through various mechanisms. These mechanisms involve blocking isoprenoid-dependent signaling pathways, regulating cytokine production, enhancing endothelial function, and reducing immune cell activation. Such actions highlight the potential role of statins in managing inflammatory disorders. Therapeutic Potential in Inflammatory Conditions: The results suggest that statins might be advantageous for both preventing and treating a range of inflammatory conditions, including multiple sclerosis (MS) and rheumatoid arthritis (RA). For instance, in MS, statins may modify T-helper cell responses,
potentially reducing neuroinflammation; meanwhile, in RA, they have been associated with a lower risk of
cardiovascular disease and all-cause mortality. Effects on Neurodegenerative Diseases: Statins are currently being evaluated for their ability to cross the blood-brain barrier and reduce neuroinflammation, which is crucial in the development of neurodegenerative conditions like Alzheimer's and Parkinson's. Existing evidence indicates that statin users show a decreased incidence of these diseases, although the findings are not yet definitive. Need for Additional Research: Despite promising results, the paper emphasizes the need for further exploration into the full therapeutic potential of statins beyond their cholesterol-lowering effects. This will entail investigating their role in various inflammatory and autoimmune disorders, as well as understanding the advantages and disadvantages of their use in these contexts.
Conflict of interests
No conflict
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 Sciences19:495–502. 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 9: https://doi.org/10.22088/IJMCM.BUMS.9.4.288
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 NS ., 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. and 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. and 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
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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and Orlandi, A., 2020. Oxidative stress and new pathogenetic mechanisms in endothelial dysfunction: potential diagnostic biomarkers and therapeutic targets. Journal of clinical medicine, 9(6), p.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. and 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. and 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. and Sahebkar, A., 2024. Targeting the CCL2–CCR2 signaling pathway: potential implications of statins beyond cardiovascular diseases. Journal of Pharmacy and Pharmacology, 76(2), pp.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., Bekiranov, S., Mulder, W.J., Gonçalves, I., Lutgens, E. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and Cervera, R., 2024. Cardiovascular disease risk in systemic lupus erythematous: certainties and controversies. Autoimmunity Reviews, 23(10),103646. https://doi.org/https://doi.org/10.1016/j.autrev.2024.103646
50. McGinley, M.P., Goldschmidt, C.H. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and 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. and Laufs, U., 2005. Pleiotropic effects of statins. Annu. Rev. Pharmacol. Toxicol., 45(1), 89-118.
63. Jain, M.K. and 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. and 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. and Mach, F., 2003. Atherosclerosis: anti-inflammatory and immunomodulatory activities of statins. Autoimmunity reviews, 2(6), 332-338.