Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. X:X | DOI: 10.5507/bp.2025.020

Potential of silymarin and its polyphenols to affect Nrf2 signalling pathway in human skin cells

Alena Rysava1, Katerina Valentova2, Katerina Cizkova3, Jitka Vostalova1, Bohumil Zalesak4, Alena Rajnochova Svobodova1
1 Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
2 Institute of Microbiology, Laboratory of Biotransformation, Academy of Sciences of the Czech Republic, Prague, Czech Republic
3 Department of Histology and Embryology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
4 Department of Plastic and Aesthetic Surgery, University Hospital Olomouc, Olomouc, Czech Republic

Introduction: Human skin is constantly exposed to various agents causing oxidative stress. In response, skin cells can activate transcriptional nuclear factor erythroid 2-related factor 2 (Nrf2), which influences the expression of several protective genes. However, accumulating evidence suggests severe adverse effects of chronic Nrf2 activation. Phytochemicals are popular for supporting skin health. Some are potent Nrf2 inducers and their long-term use may be hazardous. Silymarin (SM), an extract from Silybum marianum fruits, and its major flavonolignan silybin (SB) are used in cosmetic formulations for their protective and regenerative activities. However, knowledge about their potential to modulate Nrf2-driven pathway in skin cells or tissue is lacking.

Methods: Here we evaluated effects of SM, SB, silychristin (SC), silydianin (SD), isosilybin (ISB) and 2,3-dehydrosilybin (DHSB) and taxifolin (TA) on Nrf2 nuclear translocation, the level of Nrf2-control proteins (Keap1 and Bach1) and selected Nrf2-driven genes (NAD(P)H:quinone oxidoreductase 1 and heme oxygenase 1) in human primary fibroblasts and keratinocytes.

Results: SM and its components significantly stimulated Nrf2 nuclear translocation; SM and SB were most potent on both cell types. The effect of SM and compounds was more pronounced in fibroblasts than on keratinocytes. Regardless, effects of SM and studied compounds on the Nrf2 regulating and Nrf2-controled proteins were non-significant.

Conclusion: SM and its components do not have a significant effect on the studied proteins, and seem to be safe with respect to possible negative effects associated with the Nrf2 signalling pathway activation during dermal application. However, we cannot give a definitive answer on their effect after repeated long-term application to the whole skin. Further experiments on human skin ex vivo or clinical studies on volunteers are necessary.

Keywords: flavonolignan, flavonoid, nuclear factor erythroid 2-related factor 2, primary fibroblasts, primary keratinocytes, silymarin

Received: February 14, 2025; Revised: May 18, 2025; Accepted: June 27, 2025; Prepublished online: July 25, 2025 

Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. . Gęgotek A, Skrzydlewska E. The role of transcription factor Nrf2 in skin cells metabolism. Arch Dermatol Res 2015;307(5):385-96. Go to original source... Go to PubMed...
    2. . Ryšavá A, Vostálová J, Rajnochová Svobodová A. Effect of ultraviolet radiation on the Nrf2 signaling pathway in skin cells. Int J Radiat Biol 2021; 97(10):1383-403. Go to original source... Go to PubMed...
    3. . Schäfer M, Willrodt AH, Kurinna S, Link AS, Farwanah H, Geusau A, Gruber F, Sorg O, Huebner AJ, Roop DR, Sandhoff K, Saurat JH, Tschachler E, Schneider MR, Langbein L, Bloch W, Beer HD, Werner S. Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice. EMBO Mol Med 2014;6(4):442-57. Go to original source... Go to PubMed...
    4. . Schäfer M, Farwanah H, Willrodt AH, Huebner AJ, Sandhoff K, Roop D, Hohl D, Bloch W, Werner S. Nrf2 links epidermal barrier function with antioxidant defense. EMBO Mol Med 2012;4(5):364-79. Go to original source... Go to PubMed...
    5. . Camini FC, Costa DC. Silymarin: not just another antioxidant. J Basic Clin Physiol Pharmacol. 2020;31(4):/j/jbcpp.2020.31.issue-4/jbcpp-2019-0206/jbcpp-2019-0206.xml. doi: 10.1515/jbcpp-2019-0206 Go to original source... Go to PubMed...
    6. . Simanek V, Kren V, Ulrichova J, Vicar J, Cvak L. Silymarin: What is in the name...? An appeal for a change of editorial policy. Hepatology 2000;32(2):442-4. Go to original source...
    7. . Surai PF. Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives. Antioxidants (Basel) 2015;4(1):204-47. Go to original source... Go to PubMed...
    8. . Kim J, Lee YN, Lee J, Lee SG, Kim H, Choi YS, Draelos ZD, Kim J. Efficacy and safety of silymarin containing antioxidant serum as an adjuvant treatment of mild-to-moderate acne vulgaris: A prospective, open-label pilot study. J Cosmet Dermatol 2023;22(2):561-8. Go to original source... Go to PubMed...
    9. . NaturBites. Available from: https://www.naturbites.cz/p/olivovy-denni-krem-s-vytazky-z-pinie-a-mlekem-z-bodlaku-50ml [accessed on Dec 1, 2024] (In Czech)
    10. . Banobagi. Available from: http://shop3.banobagico.cafe24.com [accessed on Dec 1, 2024]
    11. . PCA skin. Available from: https://www.pcaskin.com/products/dual-action-redness-relief [accessed on Dec 1, 2024]
    12. . SynCare. https://www.syncare.cz/obchod/cistici-gel-anti-akne [accessed on Dec 1, 2024] (In Czech)
    13. . Eucerin. Available from: https://www.eucerin.cz/nas-vyzkum/vedecke-pozadi/elasticity-filler [accessed on Dec 1, 2024] (In Czech)
    14. . Arafa Keshk W, Zahran SM, Katary MA, Abd-Elaziz Ali D. Modulatory effect of silymarin on nuclear factor-erythroid-2-related factor 2 regulated redox status, nuclear factor-κB mediated inflammation and apoptosis in experimental gastric ulcer. Chem Biol Interact 2017;273:266-72. Go to original source... Go to PubMed...
    15. . Zhao F, Shi D, Li T, Li L, Zhao M. Silymarin attenuates paraquat-induced lung injury via Nrf2-mediated pathway in vivo and in vitro. Clin Exp Pharmacol Physiol 2015;42(9):988-98. Go to original source... Go to PubMed...
    16. . Muthumani M, Prabu SM. Silibinin potentially attenuates arsenic-induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. Cardiovasc Toxicol 2014;14(1):83-97. Go to original source... Go to PubMed...
    17. . Li L, Sun HY, Liu W, Zhao HY, Shao ML. Silymarin protects against acrylamide-induced neurotoxicity via Nrf2 signalling in PC12 cells. Food Chem Toxicol 2017;102:93-101. Go to original source... Go to PubMed...
    18. . Rajnochová Svobodová A, Ryšavá A, Čížková K, Roubalová L, Ulrichová J, Vrba J, Zálešák B, Vostálová J. Effect of the flavonoids quercetin and taxifolin on UVA-induced damage to human primary skin keratinocytes and fibroblasts. Photochem Photobiol Sci 2022;21(1):59-75. Go to original source... Go to PubMed...
    19. . Vostálová J, Tinková E, Biedermann D, Kosina P, Ulrichová J, Rajnochová Svobodová A. Skin Protective Activity of Silymarin and its Flavonolignans. Molecules 2019; 24(6):1022. Go to original source... Go to PubMed...
    20. . Křenek K, Marhol P, Peikerová Ž, Křen V, Biedermann D. Preparatory separation of the silymarin flavonolignans by Sephadex LH-20 gel. Food Res Int 2014;65:115-20. Go to original source...
    21. . Gažák R, Trouillas P, Biedermann D, Fuksová K, Marhol P, Kuzma M, Křen V. Base-catalyzed oxidation of silybin and isosilybin into 2, 3-dehydro derivatives. Tetrahedron Lett 2013;54:315-17. Go to original source...
    22. . Rajnochová Svobodová A, Gabrielová E, Michaelides L, Kosina P, Ryšavá A, Ulrichová J, Zálešák B, Vostálová J. UVA-photoprotective potential of silymarin and silybin. Arch Dermatol Res 2018;310(5):413-24. Go to original source... Go to PubMed...
    23. . Minner F, Herphelin F, Poumay Y. Study of epidermal differentiation in human keratinocytes cultured in autocrine conditions. Methods Mol Biol 2010;585:71-82. Go to original source... Go to PubMed...
    24. . Pivodová V, Franková J, Galandáková A, Ulrichová J. In Vitro AuNPs' cytotoxicity and their effect on wound healing. Nanobiomedicine (Rij) 2015;2:7. Go to original source... Go to PubMed...
    25. . Zdarilová A, Svobodová A, Simánek V, Ulrichová J. Prunella vulgaris extract and rosmarinic acid suppress lipopolysaccharide-induced alteration in human gingival fibroblasts. Toxicol In Vitro 2009;23(3):386-92. Go to original source... Go to PubMed...
    26. . Ambrožová N, Zálešák B, Ulrichová J, Čížková K, Galandáková A. Low concentrations of silver nanoparticles have a beneficial effect on wound healing in vitro. J Nanopart Res 2017;19:108. Go to original source...
    27. . Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, McQuaid S, Gray RT, Murray LJ, Coleman HG, James JA, Salto-Tellez M, Hamilton PW. QuPath: Open source software for digital pathology image analysis. Sci Rep 2017;7:16878. Go to original source... Go to PubMed...
    28. . Singh RP, Agarwal R. Mechanisms and preclinical efficacy of silibinin in preventing skin cancer. Eur J Cancer 2005;41(13):1969-79. Go to original source... Go to PubMed...
    29. . Vaid M, Katiyar SK. Molecular mechanisms of inhibition of photocarcinogenesis by silymarin, a phytochemical from milk thistle (Silybum marianum L. Gaertn.) (Review). Int J Oncol 2010;36(5):1053-60. Go to original source... Go to PubMed...
    30. . Dorjay K, Arif T, Adil M. Silymarin: An interesting modality in dermatological therapeutics. Indian J Dermatol Venereol Leprol 2018; 84(2):238-43. Go to original source... Go to PubMed...
    31. . Cohen G, Jakus J, Baroud S, Gvirtz R, Rozenblat S. Development of an Effective Acne Treatment Based on CBD and Herbal Extracts: Preliminary In Vitro, Ex Vivo, and Clinical Evaluation. Evid Based Complement Alternat Med 2023;2023:4474255. Go to original source... Go to PubMed...
    32. . Rajnochová Svobodová A, Gabrielová E, Ulrichová J, Zálešák B, Biedermann D, Vostálová J. A pilot study of the UVA-photoprotective potential of dehydrosilybin, isosilybin, silychristin, and silydianin on human dermal fibroblasts. Arch Dermatol Res 2019;311(6):477-90. Go to original source... Go to PubMed...
    33. . Hu R, Jia WY, Xu SF, Zhu ZW, Xiao Z, Yu SY, Li J. Xiaochaihutang Inhibits the Activation of Hepatic Stellate Cell Line T6 Through the Nrf2 Pathway. Front Pharmacol 2019;9:1516. Go to original source... Go to PubMed...
    34. . Zhou J, Chao G, Li Y, Wu M, Zhong S, Feng Z. Activation of NRF2/ARE by isosilybin alleviates Aβ25-35-induced oxidative stress injury in HT-22 cells. Neurosci Lett 2016;632:92-7. Go to original source... Go to PubMed...
    35. . Kang J, Jeong MG, Oh S, Jang EJ, Kim HK, Hwang ES. A FoxO1-dependent, but NRF2-independent induction of heme oxygenase-1 during muscle atrophy. FEBS Lett 2014; 588(1):79-85. Go to original source... Go to PubMed...
    36. . Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, et al. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J 2002;21(19):5216-24. Go to original source... Go to PubMed...
    37. . Casares L, García V, Garrido-Rodríguez M, Millán E, Collado JA, García-Martín A, Peñarando J, Calzado MA, de la Vega L, Muñoz E. Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol 2020;28:101321. Go to original source... Go to PubMed...
    38. . Bello M. Structural basis of Nrf2 activation by flavonolignans from silymarin. J Mol Graph Model 2023;119:108393. Go to original source... Go to PubMed...
    39. . Mehrab-Mohseni M, Sendi H, Steuerwald N, Ghosh S, Schrum LW, Bonkovsky HL. Legalon-SIL downregulates HCV core and NS5A in human hepatocytes expressing full-length HCV. World J Gastroenterol 2011;17(13):1694-700. Go to original source... Go to PubMed...
    40. . Bonifaz V, Shan Y, Lambrecht RW, Donohue SE, Moschenross D, Bonkovsky HL. Effects of silymarin on hepatitis C virus and haem oxygenase-1 gene expression in human hepatoma cells. Liver Int 2009;29(3):366-73. Go to original source... Go to PubMed...
    41. . Gazák R, Svobodová A, Psotová J, Sedmera P, Prikrylová V, Walterová D, Kren V. Oxidised derivatives of silybin and their antiradical and antioxidant activity. Bioorg Med Chem 2004;12(21):5677-87. Go to original source... Go to PubMed...
    42. . Osorio E, Pérez EG, Areche C, Ruiz LM, Cassels BK, Flórez E, Tiznado W. Why is quercetin a better antioxidant than taxifolin? Theoretical study of mechanisms involving activated forms. J Mol Model 2013;19(5):2165-72. Go to original source... Go to PubMed...
    43. . Rice-Evans CA, Miller NJ. Antioxidant activities of flavonoids as bioactive components of food. Biochem Soc Trans 1996;24(3):790-5. Go to original source... Go to PubMed...
    44. . Lee-Hilz YY, Boerboom AM, Westphal AH, Berkel WJ, Aarts JM, Rietjens IM. Pro-oxidant activity of flavonoids induces ­EpRE-mediated gene expression. Chem Res Toxicol 2006;19(11):1499-505. Go to original source... Go to PubMed...
    45. . Maini S, Fahlman BM, Krol ES. Flavonols Protect Against UV Radiation-Induced Thymine Dimer Formation in an Artificial Skin Mimic. J Pharm Pharm Sci 2015;18(4):600-15. Go to original source... Go to PubMed...
    46. . Filipe P, Silva JN, Haigle J, Freitas JP, Fernandes A, Santus R, Morlière P. Contrasting action of flavonoids on phototoxic effects induced in human skin fibroblasts by UVA alone or UVA plus cyamemazine, a phototoxic neuroleptic. Photochem Photobiol Sci 2005;4(5):420-8. Go to original source... Go to PubMed...

    This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits use, distribution, and reproduction in any medium, provided the original publication is properly cited. No use, distribution or reproduction is permitted which does not comply with these terms.


    Return