Silymarin exerts antipsoriatic effects against imiquimod-induced psoriasis in mice via NF-kB/TLR4 signaling pathway

Document Type : Original Article

Authors

1 Student Research Committee, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran

2 Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

3 Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

4 Research Group on Community Nutrition and Oxidative Stress (NUCOX) and Health Research Institute of Balearic Islands (IdISBa), University of Balearic Islands-IUNICS, Palma de Mallorca E-07122, Balearic Islands, Spain

5 CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain

10.22038/ijbms.2025.87874.18981

Abstract

Objective(s): Psoriasis is an autoimmune disease that mainly affects the skin and joints, which is mediated via T-cells. Several factors contribute to its pathogenesis, including genetic and environmental triggers, as well as intrinsic immune processes that lead to an autoimmune response. Silymarin, a flavonoid complex extracted from Silybum marianum, exhibits anti-inflammatory, immunostimulatory, and anti-oxidant properties, rendering it a viable candidate for treating psoriasis.This study aimed to investigate the effect of silymarin on imiquimod (IMQ) induced psoriasis-like skin lesions in male mice applied as a cream for seven consecutive days (1 mg per mouse).
Materials and Methods: Thirty-five male mice were assigned to seven groups (n=5 per group): (I) control group, (II) IMQ group, (III-V) oral silymarin groups (30, 60, and 120 mg/kg), (VI) topical betamethasone group, and (VII) topical silymarin 2% group. 
Results: Silymarin, both orally and topically, significantly reduces erythema, thickness, and scaling induced by IMQ after seven days of treatment. The treatment also reversed the increase in spleen weight/body weight ratio. Immunofluorescence analysis revealed that silymarin reduced the expression of nuclear factor κB (NF-κB) (P<0.01) and toll-like receptor 4 (TLR4) (P<0.01) compared to the IMQ group.
Conclusion: These findings suggest that silymarin effectively alleviates psoriasis lesions by reducing inflammation and modulating the TLR4/ NF-κB signaling pathway.

Keywords

Main Subjects

References

1. Boehncke WH, Schön MP. Psoriasis. Lancet. 2015;386:983-994.
2. Schäkel K, Schön MP, Ghoreschi K. Pathogenesis of psoriasis. Hautarzt 2016;67:422-431.
3. Branisteanu DE, Cojocaru C, Diaconu R, Porumb EA, Alexa AI, Nicolescu AC, et al. Update on the etiopathogenesis of psoriasis (Review). Exp Ther Med 2022;23:201-214.
4. Jin Z, Huang Q, Peng J, Liu Z, Hu R, Wu J, et al. MiR-125a-3p alleviates hyperproliferation of keratinocytes and psoriasis-like inflammation by targeting TLR4/NF-κB pathway. Postepy Dermatol Alergol 2023;40:447-461.
5. Lee HJ, Kim M. Challenges and future trends in the treatment of psoriasis. Int J Mol Sci 2023;24:13313.
6. Rujimongkon K, Ampawong S, Reamtong O, Buaban T, Aramwit P. The therapeutic effects of Bombyx mori sericin on rat skin psoriasis through modulated epidermal immunity and attenuated cell proliferation. J Tradit Complement Med 2021;11:587-597.
7. Rendon A, Schäkel K. Psoriasis pathogenesis and treatment. Int J Mol Sci 2019; 20:1-12.
8. Tokuyama M, Mabuchi T. New treatment addressing the pathogenesis of psoriasis. Int J Mol Sci 2020;21:7488-7503.
9. Kawai T, Akira S. TLR signaling. Semin Immunol 2007;19:24-32.
10. Takeda K, Akira S. Toll-like receptors in innate immunity. Int J Mol Sci 2005;17:1-14.
11. Panzer R, Blobel C, Fölster‐Holst R, Proksch E. TLR 2 and TLR 4 expression in atopic dermatitis, contact dermatitis and psoriasis. Exp Dermatol 2014;23:364-366.
12. Shehata W, Hammam M, Seif D, Elsayed S, Maqsoud E, El-Hefnawy S. Role of Toll-like receptor 4 gene expression in psoriasis and its relation to disease activity. Menoufia Med J 2022;35:418-423.
13. Dolcet X, Llobet D, Pallares J, Matias-Guiu X. NF-kB in development and progression of human cancer. Virchows Arch 2005;446:475-482.
14. Gaptulbarova KA, Tsyganov MM, Pevzner AM, Ibragimova MK, Litviakov NV. NF-kB as a potential prognostic marker and a candidate for targeted therapy of cancer. Exp Oncol 2020;42:263-269.
15. Moorchung N, Kulaar JS, Chatterjee M, Vasudevan B, Tripathi T, Dutta V. Role of NF-κB in the pathogenesis of psoriasis elucidated by its staining in skin biopsy specimens. Int J Dermatol 2014;53:570-574.
16. Ogawa E, Sato Y, Minagawa A, Okuyama R. Pathogenesis of psoriasis and development of treatment. J Dermatol 2018;45:264-272.
17. Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PF. NF-κB: An essential transcription factor in psoriasis. J Dermatol Sci 2013;69:89-94.
18. van der Fits L, Mourits S, Voerman JSA, Kant M, Boon L, Laman JD, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis1. J Immunol 2009;182:5836-5845.
19. Gao J, Chen F, Fang H, Mi J, Qi Q, Yang M. Daphnetin inhibits proliferation and inflammatory response in human HaCaT keratinocytes and ameliorates imiquimod-induced psoriasis-like skin lesion in mice. Biol Res 2020;53:48-60.
20.    Greaves MW, Weinstein GD. Treatment of psoriasis. NEJM 1995;332:581-589.
21. Rahman M, Alam K, Ahmad MZ, Gupta G, Afzal M, Akhter S, et al. Classical to current approach for treatment of psoriasis: A review. Endocr Metab Immune Disord Drug Targets 2012;12:287-302.
22. Rapalli VK, Sharma S, Roy A, Singhvi G. Design and dermatokinetic evaluation of Apremilast loaded nanostructured lipid carriers embedded gel for topical delivery: A potential approach for improved permeation and prolong skin deposition. Colloids Surf. B Biointerfaces 2021;206:111945.
23. Mitra A, Wu Y. Topical delivery for the treatment of psoriasis. Expert Opin Drug Deliv 2010;7:977-992.
24. Feldman SR, Horn EJ, Balkrishnan R, Basra MK, Finlay AY, McCoy D, et al. Psoriasis: Improving adherence to topical therapy. J Am Acad Dermatol 2008;59:1009-1016.
25. Zschocke I, Mrowietz U, Karakasili E, Reich K. Non-adherence and measures to improve adherence in the topical treatment of psoriasis. J Eur Acad Dermatol Venereol 2014;28:4-9.
26. Wadhwa K, Pahwa R, Kumar M, Kumar S, Sharma PC, Singh G, et al. Mechanistic insights into the pharmacological significance of silymarin. Molecules 2022;27:5327-5377.
27. Dobrzynska M, Napierala M, Florek E. Flavonoid nanoparticles: A promising approach for cancer therapy. Biomolecules 2020;10: 1268-1285.
28. Ebrahimi A, Mehrabi M, Miraghaee SS, Mohammadi P, Fatehi Kafash F, Delfani M, et al. Flavonoid compounds and their synergistic effects: Promising approaches for the prevention and treatment of psoriasis with emphasis on keratinocytes – A systematic and mechanistic review. Int Immunopharmacol 2024;138:112561.
29. Alalaiwe A, Lin C-F, Hsiao C-Y, Chen E-L, Lin C-Y, Lien W-C, et al. Development of flavanone and its derivatives as topical agents against psoriasis: The prediction of therapeutic efficiency through skin permeation evaluation and cell-based assay. Int J Pharm 2020;581:119256.
30. Zholobenko A, Modriansky M. Silymarin and its constituents in cardiac preconditioning. Fitoterapia. 2014;97:122-132.
31. Koltai T, Fliegel L. Role of silymarin in cancer treatment: Facts, hypotheses, and questions. J Evid Based Integr Med 2022;27:1-38.
32. Chambers CS, Holečková V, Petrásková L, Biedermann D, Valentová K, Buchta M, et al. The silymarin composition… and why does it matter???. Food Res Int 2017;100:339-353.
33. Karimi G, Vahabzadeh M, Lari P, Rashedinia M, Moshiri M. “Silymarin”, a promising pharmacological agent for treatment of diseases. Iran J Basic Med Sci 2011;14:308-317.
34. Comelli MC, Mengs U, Schneider C, Prosdocimi M. Toward the definition of the mechanism of action of silymarin: Activities related to cellular protection from toxic damage induced by chemotherapy. Integr Cancer Ther 2007;6:120-129.
35. Rostamian S, Heidari-Soureshjani S, Sherwin CMT. The therapeutic effect of silymarin and silibinin on depression and anxiety disorders and possible mechanism in the brain: a systematic review. Cent Nerv Syst Agents Med Chem 2023;23:86-94.
36. Yi M, Manzoor M, Yang M, Zhang H, Wang L, Zhao L, et al. Silymarin targets the FXR protein through microbial metabolite 7-keto-deoxycholic acid to treat MASLD in obese mice. Phytomedicine 2024;133:155947.
37. Piazzini V, D’Ambrosio M, Luceri C, Cinci L, Landucci E, Bilia AR, et al. Formulation of nanomicelles to improve the solubility and the oral absorption of silymarin. Molecules 2019;24:1688-1707.
38. Taleb A, Ahmad KA, Ihsan AU, Qu J, Lin N, Hezam K, et al. Antioxidant effects and mechanism of silymarin in oxidative stress induced cardiovascular diseases. Biomed Pharmacother 2018;102:689-698.
39. Dixit N, Baboota S, Kohli K, Ahmad S, Ali J. Silymarin: A review of pharmacological aspects and bioavailability enhancement approaches. Indian J Pharmacol 2007;39:172-179.
40. Kshirsagar AD, Ingawale DK, Ashok P, Vyawahare NS. Silymarin: A comprehensive review. Phcog Rev 2009;3:116-124.
41. Radko L, Cybulski WA. Application of silymarin in human and animal medicine. J Pre-Clin Res 2007;01:22-26.
42. Tabari SA, Carpi S, Polini B, Nieri P, Esfahani ML, Moghadamnia AA, et al. Topical application of silymarin enhances cutaneous wound healing in rats. S Afr J Bot 2019;124:494-498.
43. Noori T, Sureda A, Shirooie S. Ivermectin decreases inflammation and imiquimod–induced psoriasis-like skin lesions in rat via targeting TLR4/p65 NF-κB. Iran J Basic Med Sci 2025;28:808-814.
44. Guo Y, Wang S, Wang Y, Zhu T. Silymarin improved diet-induced liver damage and insulin resistance by decreasing inflammation in mice. Pharm Biol 2016;54:2995-3000.
45. Stolf AM, Cardoso CC, Acco A. Effects of silymarin on diabetes mellitus complications: A review. Phytother Res 2017;31:366-374.
46. Schäfer I, Hacker J, Rustenbach SJ, Radtke M, Franzke N, Augustin M. Concordance of the psoriasis area and severity index (PASI) and patient-reported outcomes in psoriasis treatment. Eur J Dermatol 2010;20:62-67.
47. Okasha EF, Bayomy NA, Abdelaziz EZ. Effect of topical application of black seed oil on imiquimod-induced psoriasis-like lesions in the thin skin of adult male albino rats. The Anat Rec 2018;301:166-174.
48. Frenzel DF, Borkner L, Scheurmann J, Singh K, Scharffetter-Kochanek K, Weiss JM. Osteopontin deficiency affects imiquimod-induced psoriasis-like murine skin inflammation and lymphocyte distribution in skin, draining lymph nodes and spleen. Exp Dermatol 2015;24:305-307.
49. Li TY, Liang WL, Zhao YM, Chen WD, Zhu HX, Duan YY, et al. Alpha-Pinene-encapsulated lipid nanoparticles diminished inflammatory responses in THP-1 cells and imiquimod-induced psoriasis-like skin injury and splenomegaly in mice. Front Immunol 2024;15:1390589.
50. Li XP, Liu P, Li YF, Zhang GL, Zeng DS, Liu DL. LPS induces activation of the TLR4 pathway in fibroblasts and promotes skin scar formation through collagen I and TGF-β in skin lesions. Int J Clin Exp Pathol 2019;12:2121-2129.
51. Yao L, Kan EM, Lu J, Hao A, Dheen ST, Kaur C, et al. Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: Role of TLR4 in hypoxic microglia. J Neuroinflammation 2013;10:785-806.
52. Katiyar SK. Silymarin and skin cancer prevention: Anti-inflammatory, antioxidant and immunomodulatory effects (Review). Int J Oncol 2005;26:169-176.
53. Esmaeil N, Anaraki SB, Gharagozloo M, Moayedi B. Silymarin impacts on immune system as an immunomodulator: One key for many locks. Int Immunopharmacol 2017;50:194-201.
54. Weinstein GD, McCullough JL, Ross PA. Cell kinetic basis for pathophysiology of psoriasis. J Invest Dermatol 1985;85:579-583.
55. Singh RP, Agarwal R. Flavonoid antioxidant silymarin and skin cancer. Antioxid Redox Signal 2002;4:655-663.
56. Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PF. NF-κB: an essential transcription factor in psoriasis. J Dermatol Sci 2013;69:89-94.
57. Al-Rasheed NM, Fadda LM, Al-Rasheed NM, Ali HM, Yacoub HI. Down-regulation of NFkB, Bax,TGF-β, Smad-2mRNA expression in the livers of carbon tetrachloride treated rats using different natural antioxidants. Braz Arch Biol Technol 2016;59:1-10.
58. Altindağ F. Silymarin ameliorates cisplatin-induced nephrotoxicity by downregulating TNF-α and NF-kB and by upregulating IL-10. J Exp Clin Med 2022;39:216-220.
59.    He X, Wei Z, Zhou E, Chen L, Kou J, Wang J, et al. Baicalein attenuates inflammatory responses by suppressing TLR4 mediated NF-κB and MAPK signaling pathways in LPS-induced mastitis in mice. Int Immunopharmacol 2015;28:470-476.
60. Linh NTT, Giang NH, Lien NTK, Trang BK, Trang DT, Ngoc NT, et al. Association of PSORS1C3, CARD14 and TLR4 genotypes and haplotypes with psoriasis susceptibility. Genet Mol Biol 2022;45:1-14.
61. Saleh HA, Yousef MH, Abdelnaser A. The anti-inflammatory properties of phytochemicals and their effects on epigenetic mechanisms involved in TLR4/NF-κB-mediated inflammation. Front Immunol 2021;12:1-29.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 11
November 2025
Pages 1523-1530

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