Thymoquinone as a Natural Anti-Angiogenic Agent: Experimental Pharmacology insights into Schematic and Meta-Analysis of Ocular Neovascularization and Retinal Pathology

Authors

  • Soobia Pathan Liaquat Institute of Medical and Health Sciences LUMHS, Thatta (Sindh), Pakistan.
  • Anaam Rehman Rawal Institute of Health Sciences, Rawal College of Medicine, Islamabad, Pakistan.
  • Syed Azhar Hussain Zaidi Bolan university of medical and Health sciences Quetta Pakistan.
  • Muhammad Imran Ali king khalid Hospital, Al-Majmaah, Kingdom of Saudi Arabia

DOI:

https://doi.org/10.36283/ziun-pjmd14-3/057

Keywords:

Thymoquinone, Retinal Neovascularization, Corneal Neovascularization, Neovascularization, Pathologic, Vascular Endothelial Growth Factors, Diabetic Retinopathy, Oxidative Stress, Angiogenesis, Anti‑Angiogenic Agents, Meta‑Analysis.

Abstract

Background: Thymoquinone is seen to combat angiogenesis, reduce inflammation, and act as an antioxidant. This systematic review and meta-analysis aimed to assess the role of thymoquinone in angiogenesis, damage involving reactive oxygen species, and preservation of the retina in different preclinical models.

Methods: This study followed the PRISMA approach, and PubMed, Scopus, Web of Science, and Cochrane Library were searched to identify studies published by 2025. This study included in vivo and in vitro studies examining how thymoquinone influences the growth of new blood vessels in different cell lines and animal models. Excluded studies were reviews, case studies, reports, and studies in a non-English language. For quality assessment, the OHAT risk of bias assessment tool was used, and effect sizes were measured to determine the therapeutic role of thymoquinone on eye diseases. GRADE framework was employed to assess the certainty of evidence.

Results: Ten preclinical articles were reviewed to assess the impacts of thymoquinone on ocular angiogenesis. Meta-analysis demonstrated an in vivo and in vitro pooled effective concentration of 32.31 and 7.37 μM, respectively. Effect sizes were in constant support of the antioxidant and anti-inflammatory properties of thymoquinone. Bias across studies was low, and on GRADE assessment, it had moderate certainty, having therapeutic potential in neovascular retinal disorders. Discussion: Overall, thymoquinone appears useful in reducing the formation of new blood vessels and reducing oxidative damage in diseases affecting the eyes. Because it seems promising in the role of a treatment supplement, more research through clinical studies should be carried out.

Author Biographies

  • Soobia Pathan, Liaquat Institute of Medical and Health Sciences LUMHS, Thatta (Sindh), Pakistan.

    Department of Pharmacology and Therapeutics,

  • Anaam Rehman, Rawal Institute of Health Sciences, Rawal College of Medicine, Islamabad, Pakistan.

    Department of ophthalmology, 

  • Syed Azhar Hussain Zaidi, Bolan university of medical and Health sciences Quetta Pakistan.

    Department of Pharmacology,


  • Muhammad Imran Ali, king khalid Hospital, Al-Majmaah, Kingdom of Saudi Arabia

    Department of Ophthalmology, 

References

1. Pennisi F, Gentile L, Borlini S, Gianfredi V, Signorelli C. Direct and indirect healthcare costs of ocular diseases in Italy: a literature review on glaucoma, diabetic retinopathy, and macular degeneration. Ann Ig. 2025 Jul-Aug;37(4):532-555. doi: 10.7416/ai.2025.2676.

2. Huang D, Liu Z, Deng Y. Retinopathy of Prematurity (ROP): An Overview of Biomarkers in Various Samples for Prediction, Diagnosis, and Prognosis. Clin Ophthalmol. 2025 May 7;19:1515-1530. doi: 10.2147/OPTH.S519292.

3. Wang L, Liu W-Q, Broussy S, Han B, Fang H. Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis. Front Pharmacol. 2024 Jan 4;14:1307860. doi:10.3389/fphar.2023.1307860.

4. Kanadani T, Rabelo N, Takahashi D, Magalhães L, Farah M. Comparison of antiangiogenic agents (ranibizumab, aflibercept, bevacizumab and ziv-aflibercept) in the therapeutic response to the exudative form of age-related macular degeneration according to the treat-and-extend protocol—True head-to-head study. Int J Retina Vitreous. 2024 Feb 2;10(1):13. doi:10.1186/s40942-024-00537-5.

5. Ravi Y, Vethamoni PI, Saxena SN, Kaviyapriya M, Santhanakrishnan VP, Raveendran M, et al. Anticancer potential of Thymoquinone from Nigella sativa L.: An in-silico and cytotoxicity study. PLoS One. 2025 Jun 12;20(6):e0323804. doi: 10.1371/journal.pone.0323804.

6. Chatterjee G, Saha AK, Khurshid S, Saha A. A Comprehensive Review of the Antioxidant, Antimicrobial, and Therapeutic Efficacies of Black Cumin (Nigella sativa L.) Seed Oil and Its Thymoquinone. J Med Food. 2025 Apr;28(4):325-339. doi: 10.1089/jmf.2024.k.0149.

7. Hannan MA, Rahman MA, Sohag AAM, Uddin MJ, Dash R, Sikder MH, et al. Black cumin (Nigella sativa L.): A comprehensive review on phytochemistry, health benefits, molecular pharmacology, and safety. Nutrients. 2021 Jun;13(6):1784. doi:10.3390/nu13061784.

8. Mahmud NM, Paraoan L, Khaliddin N, Kamalden TA. Thymoquinone in ocular neurodegeneration: Modulation of pathological mechanisms via multiple pathways. Front Cell Neurosci. 2022 Mar 2;16:786926. doi:10.3389/fncel.2022.786926.

9. Sharma B, Shekhar H, Sahu A, Haque S, Kaur D, Tuli HS, et al. Deciphering the anticancer potential of thymoquinone: in-depth exploration of the potent flavonoid from Nigella sativa. Mol Biol Rep. 2025 Feb 28;52(1):268. doi: 10.1007/s11033-025-10375-9.

10. Rahjoo T, Motamedzadeh A, Ferdosi F, Dadgostar E, Aschner M, Mirzaei H, Ghesmatpour S, Nabavizadeh F, Rahmati-Dehkordi F, Tamtaji OR. Potential role of thymoquinone to treat gastrointestinal cancers: insights into its molecular mechanisms. Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 5. doi: 10.1007/s00210-025-03861-1.

11. Guler EM, Sisman BH, Kocyigit A, Hatiboglu MA. Investigation of cellular effects of thymoquinone on glioma cell. Toxicol Rep. 2021 Jan 4;8:162-170. doi: 10.1016/j.toxrep.2020.12.026.

12. Hamaamin KS, Marouf BH. Chemopreventive efficacy of thymoquinone in chemically induced urinary bladder carcinogenesis in rat. Biomed Res Int. 2022 Sep 15;2022:6276768. doi:10.1155/2022/6276768.

13. Liu Y, Huang L, Kim M-Y, Cho JY. The role of thymoquinone in inflammatory response in chronic diseases. Int J Mol Sci. 2022 Jan;23(18):10246. doi:10.3390/ijms231810246.

14. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 March;372:71. doi: 10.1136/bmj.n71.

15. Erguven P, Sevgin K, Kotil T, Kaleci B, Caglar HG, Ozer OF. Continuous Thymoquinone Administration Mitigates Sodium Iodate-Induced Retinal Degeneration in Rats. Curr Eye Res. 2024 Dec;49(12):1313-1321. doi: 10.1080/02713683.2024.2381203.

16. Demir E, Taysi S, Al B, Demir T, Okumus S, Saygili O, et al. The effects of Nigella sativa oil, thymoquinone, propolis, and caffeic acid phenethyl ester on radiation-induced cataract. Wien Klin Wochenschr. 2016 Dec;128(Suppl 8):587-595. doi: 10.1007/s00508-015-0736-4.

17. Kocatürk T, Erkan E, Meteoğlu İ, Ekici M, Karul Büyüköztürk A, Yavaşoğlu İ, et al. Effects of Topical Thymoquinone in an Experimental Dry Eye Model. Turk J Ophthalmol. 2018 Dec 27;48(6):281-287. doi: 10.4274/tjo.50146.

18. Fahmy HM, Saad EAES, Sabra NM, El-Gohary AA, Mohamed FF, Gaber MH. Treatment merits of Latanoprost/Thymoquinone - Encapsulated liposome for glaucomatus rabbits. Int J Pharm. 2018 Sep 5;548(1):597-608. doi: 10.1016/j.ijpharm.2018.07.012.

19. Fouad AA, Alwadani F. Ameliorative effects of thymoquinone against eye lens changes in streptozotocin diabetic rats. Environ Toxicol Pharmacol. 2015 Nov;40(3):960-5. doi: 10.1016/j.etap.2015.09.010.

20. Hayat K, Asim MBR, Nawaz M, Li M, Zhang L, Sun N. Ameliorative effect of thymoquinone on ovalbumin-induced allergic conjunctivitis in Balb/c mice. Curr Eye Res. 2011 Jul;36(7):591-598. doi:10.3109/02713683.2011.573898.

21. Paramasivam A, Kalaimangai M, Sambantham S, Anandan B, Jayaraman G. Anti-angiogenic activity of thymoquinone by the down-regulation of VEGF using zebrafish (Danio rerio) model. Biomed Prev Nutr. 2012 Jul;2(3):169–73. doi:10.1016/j.bionut.2012.03.011.

22. Sen S, Kasikci M. Low-dose rosmarinic acid and thymoquinone accelerate wound healing in retinal pigment epithelial cells. Int Ophthalmol. 2023 Oct;43(10):3811-3821. doi: 10.1007/s10792-023-02799-8.

23. Hu X, Liang Y, Zhao B, Wang Y. Thymoquinone protects human retinal pigment epithelial cells against hydrogen peroxide induced oxidative stress and apoptosis. J Cell Biochem. 2019 Mar;120(3):4514-4522. doi: 10.1002/jcb.27739.

24. Landucci E, Mazzantini C, Calvani M, Pellegrini-Giampietro DE, Bergonzi MC. Evaluation of Conventional and Hyaluronic Acid-Coated Thymoquinone Liposomes in an In Vitro Model of Dry Eye. Pharmaceutics. 2023 Feb 8;15(2):578. doi: 10.3390/pharmaceutics15020578.

25. Wahab S, Alsayari A. Potential pharmacological applications of Nigella seeds with a focus on Nigella sativa and its constituents against chronic inflammatory diseases: Progress and future opportunities. Plants. 2023 Jan;12(22):3829. doi:10.3390/plants12223829.

26. Lin JB, Apte RS. The Landscape of Vascular Endothelial Growth Factor Inhibition in Retinal Diseases. Invest Ophthalmol Vis Sci. 2025 Jan 2;66(1):47. doi: 10.1167/iovs.66.1.47.

27. Naaman E, Yanir-Prat N, Shair-Nakhleh D, Bar N, Miller B, Fishman A, et al. Exploring Factors behind Patient Nonadherence to Intravitreal Anti-Vascular Endothelial Growth Factor Injections in Macular Diseases. Ophthalmic Res. 2025;68(1):221-227. doi: 10.1159/000543352.

28. Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct Target Ther. 2025 May 19;10(1):170. doi: 10.1038/s41392-025-02249-0.

29. Bourhis M, Palle J, Galy-Fauroux I, Terme M. Direct and indirect modulation of T cells by VEGF-A counteracted by anti-angiogenic treatment. Front Immunol. 2021 Mar 29;12:616837. doi:10.3389/fimmu.2021.616837.

30. Li Z, Zhang Y. Anti-Vascular Endothelial Growth Factor Crunch Syndrome in Proliferative Diabetic Retinopathy. JCEM Case Rep. 2025 Apr 18;3(6):luaf083. doi: 10.1210/jcemcr/luaf083.

31. Lopes-Coelho F, Martins F, Pereira SA, Serpa J. Anti-angiogenic therapy: Current challenges and future perspectives. Int J Mol Sci. 2021 Apr;22(7):3765. doi:10.3390/ijms22073765.

32. Gao S, Gao S, Wang Y, Xiang L, Peng H, Chen G, et al. Inhibition of Vascular Endothelial Growth Factor Reduces Photoreceptor Death in Retinal Neovascular Disease via Neurotrophic Modulation in Müller Glia. Mol Neurobiol. 2025 May;62(5):6352-6368. doi: 10.1007/s12035-025-04689-9.

33. Gurbilek M, Deniz CD, Eroglu Gunes C, Kurar E, Reisli I, Kursunel MA, et al. Anticancer activity of thymoquinone in non-small cell lung cancer and possible involvement of PPAR-γ pathway. Int J Radiat Biol. 2025;101(4):370-381. doi: 10.1080/09553002.2025.2449953.

34. Masuda T, Shimazawa M, Hara H. Retinal diseases associated with oxidative stress and the effects of a free radical scavenger (Edaravone). Oxid Med Cell Longev. 2017;2017:9208489. doi:10.1155/2017/9208489.

35. Cui X, Buonfiglio F, Pfeiffer N, Gericke A. Aging in ocular blood vessels: Molecular insights and the role of oxidative stress. Biomedicines. 2024 Apr;12(4):817. doi:10.3390/biomedicines12040817.

36. Isaev NK, Genrikhs EE, Stelmashook EV. Antioxidant thymoquinone and its potential in the treatment of neurological diseases. Antioxidants. 2023 Feb;12(2):433. doi:10.3390/antiox12020433.

37. Kumar V, Kesharwani R, Patel DK, Verma A, Mehanna MG, Mohammad A, et al. Epigenetic Impact of Curcumin and Thymoquinone on Cancer Therapeutics. Curr Med Chem. 2025;32(11):2183-2201. doi: 10.2174/0109298673288542240327112351.

38. Pottoo FH, Ibrahim AM, Alammar A, Alsinan R, Aleid M, Alshehhi A, et al. Thymoquinone: Review of its potential in the treatment of neurological diseases. Pharmaceuticals. 2022 Apr;15(4):408. doi:10.3390/ph15040408.

39. Liu X, Huang K, Zhang F, Huang G, Wang L, Wu G, et al. Multifunctional nano-in-micro delivery systems for targeted therapy in fundus neovascularization diseases. J Nanobiotechnology. 2024 Jun;22(1):354. doi:10.1186/s12951-024-02614-1.

40. Ateş Ş, Ülger H, Uçar S, Okan A, Ocak M, Güvenilir E, et al. Evaluation of the Effects of Thymoquinone on RAGE/NOX4 Expressions and Brain Tissue Morphometry in Experimental Alzheimer's Disease Induced by Amyloid Beta 1-42 Peptide. Biomolecules. 2025 Apr 7;15(4):543. doi: 10.3390/biom15040543.

Downloads

Published

2025-07-21

Metrics

How to Cite

1.
Pathan S, Rehman A, Zaidi SAH, Ali MI. Thymoquinone as a Natural Anti-Angiogenic Agent: Experimental Pharmacology insights into Schematic and Meta-Analysis of Ocular Neovascularization and Retinal Pathology. PJMD [Internet]. 2025 Jul. 21 [cited 2026 Jun. 23];14(3):382-91. Available from: https://ojs.zu.edu.pk/pjmd/article/view/3856

Similar Articles

1-10 of 582

You may also start an advanced similarity search for this article.