A comprehensive insight into potential roles of Nigella sativa on diseases by targeting AMP-activated protein kinase: a review



Nigella sativa (NS) is a known medicinal herb with numerous therapeutic effects such as antidiabetic, anti-proliferative, anti-inflammatory, and anti-cancer activities. It has been indicated that NS can regulate cellular metabolism by adjusting transduction signaling pathways. Adenosine monophosphate-activated protein kinase (AMPK) is one of the main physiological processes, such as energy hemostasis, cellular metabolism, and autophagy regulators. Herb-derived medicines have always been considered as one of the main AMPK activators, and surprisingly recent data has demonstrated that it can be a target for NS and its derivatives.

Evidence acquisition

The literature search was conducted in PubMed, SCOPUS, Embase, ProQuest, and Google Scholar electronic resources. Published articles up to September 2020 were considered, and those of which investigated Nigella sativa effects on the AMPK pathway after meeting the inclusion criteria were included.


The search was performed on several online databases such as PubMed, Scopus, Embase, ProQuest, and Google Scholar from inception until January 2020. Among the initial search, 245 studies were found. After removing duplicated data and meeting the inclusion criteria, only 14 studies were selected. They included the effects of NS and its bioactive compounds as anti-hyperglycemic (n = 5), on liver function (n = 4), cancers (n = 3), and on Neuroinflammation and Atherosclerosis (n = 2). Most of the included studies are animals or in-vitro investigations.


In this review, we discuss the latest findings on the molecular mechanism of NS effecting the AMPK signaling pathway. We also focus on the therapeutic effects of NS, including the prevention and treatment of metabolic and pro-inflammatory disease by targeting the AMPK pathway.

Graphical abstract

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2



Acetyl-CoA carboxylase


protein kinase B


alcoholic liver disease


AMP-activated protein kinase


epithelial-mesenchymal transition


extracellular signal-regulated kinases


Forkhead box protein O1

GLUT-4 :

Glucose transporter type 4

HSCs :

Hepatic stellate cells

LKB1 :

Liver kinase B1

mTOR :

mammalian target of rapamycin

NF-kB :

nuclear factor kappa-light-chain-enhancer of activated B

NS :

Nigella sativa

PGC-1 :

Proliferator-Activated Receptor-Gamma Coactivator-1


Peroxisome Proliferator-Activated Receptor


Renal carcinoma cells


Reactive oxygen species




Transforming growth factor-beta

TLR4 :

Toll-like receptor 4

TQ :



Vascular Smooth Muscle Cell


  1. 1.

    Soltani A, Salmaninejad A, Jalili-Nik M, Soleimani A, Javid H, Hashemy SI, et al. 5′-adenosine monophosphate-activated protein kinase: a potential target for disease prevention by curcumin. J Cell Physiol. 2019;234(3):2241–51.

    CAS  PubMed  Google Scholar 

  2. 2.

    Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, et al. Structure of mammalian AMPK and its regulation by ADP. Nature. 2011;472(7342):230–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Wu D, Hu D, Chen H, Shi G, Fetahu IS, Wu F, et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature. 2018;559(7715):637–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Day EA, Ford RJ, Steinberg GR. AMPK as a therapeutic target for treating metabolic diseases. Trends Endocrinol Metab. 2017;28(8):545–60.

    CAS  PubMed  Google Scholar 

  5. 5.

    Yavari A, Stocker CJ, Ghaffari S, Wargent ET, Steeples V, Czibik G, et al. Chronic activation of γ2 AMPK induces obesity and reduces β cell function. Cell Metab. 2016;23(5):821–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Gholamnezhad Z, Havakhah S, Boskabady MH. Preclinical and clinical effects of Nigella sativa and its constituent, thymoquinone: a review. J Ethnopharmacol. 2016;190:372–86.

    CAS  PubMed  Google Scholar 

  7. 7.

    Majdalawieh AF, Fayyad MW. Immunomodulatory and anti-inflammatory action of Nigella sativa and thymoquinone: a comprehensive review. Int Immunopharmacol. 2015;28(1):295–304.

    CAS  PubMed  Google Scholar 

  8. 8.

    Jeon S-M. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48(7):e245–e.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Fogarty S, Hardie D. Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochimica et biophysica Acta (bba)-Prot Proteom. 2010;1804(3):581–91.

    CAS  Google Scholar 

  10. 10.

    Kazyken D, Magnuson B, Bodur C, Acosta-Jaquez HA, Zhang D, Tong X, et al. AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. Sci Signal, 2019;12(585):eaav3249.

  11. 11.

    Zhang Y, Fan Y, Huang S, Wang G, Han R, Lei F, et al. Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway. Cancer Sci. 2018;109(12):3865–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Deeks JJ, Higgins J, Altman DG, Green S. Cochrane handbook for systematic reviews of interventions version 5.1. 0 (updated March 2011). Cochrane Collab. 2011; 2.

  13. 13.

    Acevedo D, Varela E, Guerra J, Banu J, Reyna S. Nigella sativa influences GLUT4 through the AMPK pathway. FASEB J. 2015;29(1_supplement):608–27.

    Google Scholar 

  14. 14.

    Yuan T, Nahar P, Sharma M, Liu K, Slitt A, Aisa H, et al. Indazole-type alkaloids from Nigella sativa seeds exhibit antihyperglycemic effects via AMPK activation in vitro. J Nat Prod. 2014;77(10):2316–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Benhaddou-Andaloussi A, Martineau L, Vuong T, Meddah B, Madiraju P, Settaf A, et al. The in vivo antidiabetic activity of Nigella sativa is mediated through activation of the AMPK pathway and increased muscle Glut4 content. Evid Based Complement Alternat Med. 2011;2011:1–9.

    Google Scholar 

  16. 16.

    Benhaddou-Andaloussi A, Martineau L, Vallerand D, Haddad Y, Afshar A, Settaf A, et al. Multiple molecular targets underlie the antidiabetic effect of Nigella sativa seed extract in skeletal muscle, adipocyte and liver cells. Diabetes Obes Metab. 2010;12(2):148–57.

    CAS  PubMed  Google Scholar 

  17. 17.

    Ali B, Louis MC, Diane V, Yara H, Pierre HS. Antidiabetic effects of Nigella sativa are mediated by activation of insulin and AMPK pathways, and by mitochondrial uncoupling. Can J Diabetes. 2008;32(4):333.

    Google Scholar 

  18. 18.

    Haas MJ, Onstead-Haas L, Naem E, Arnold A, Rohrbaugh N, Flowers M, et al. The effect of black seed (Nigella sativa) extract on FOXO3 expression in HepG2 cells. Phytother Res. 2014;28(6):873–9.

    PubMed  Google Scholar 

  19. 19.

    Bai T, Yang Y, Wu Y-L, Jiang S, Lee JJ, Lian L-H, et al. Thymoquinone alleviates thioacetamide-induced hepatic fibrosis and inflammation by activating LKB1–AMPK signaling pathway in mice. Int Immunopharmacol. 2014;19(2):351–7.

    CAS  PubMed  Google Scholar 

  20. 20.

    Cui B-W, Bai T, Yang Y, Zhang Y, Jiang M, Yang H-X, et al. Thymoquinone attenuates acetaminophen overdose-induced acute liver injury and inflammation via regulation of JNK and AMPK signaling pathway. Am J Chin Med. 2019;47(03):577–94.

    CAS  PubMed  Google Scholar 

  21. 21.

    Yang Y, Bai T, Yao Y-L, Zhang D-Q, Wu Y-L, Lian L-H, et al. Upregulation of SIRT1-AMPK by thymoquinone in hepatic stellate cells ameliorates liver injury. Toxicol Lett. 2016;262:80–91.

    CAS  PubMed  Google Scholar 

  22. 22.

    Kou B, Kou Q, Ma B, Zhang J, Sun B, Yang Y, et al. Thymoquinone inhibits metastatic phenotype and epithelial-mesenchymal transition in renal cell carcinoma by regulating the LKB1/AMPK signaling pathway. Oncol Rep. 2018;40(3):1443–50.

    CAS  PubMed  Google Scholar 

  23. 23.

    Velagapudi R, El-Bakoush A, Lepiarz I, Ogunrinade F, Olajide OA. AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2 microglia. Mol Cell Biochem. 2017;435(1–2):149–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Pei X, Li X, Chen H, Han Y, Fan Y. Thymoquinone inhibits angiotensin II-induced proliferation and migration of vascular smooth muscle cells through the AMPK/PPARγ/PGC-1α pathway. DNA Cell Biol. 2016;35(8):426–33.

    CAS  PubMed  Google Scholar 

  25. 25.

    Islam MT, Khan MR, Mishra SK. An updated literature-based review: phytochemistry, pharmacology and therapeutic promises of Nigella sativa L. Orient Pharm Exp Med. 2019:1–15.

  26. 26.

    Kooti W, Hasanzadeh-Noohi Z, Sharafi-Ahvazi N, Asadi-Samani M, Ashtary-Larky D. Phytochemistry, pharmacology, and therapeutic uses of black seed (Nigella sativa). Chin J Nat Med. 2016;14(10):732–45.

    CAS  PubMed  Google Scholar 

  27. 27.

    Mazaheri Y, Torbati M, Azadmard-Damirchi S, Savage GP. A comprehensive review of the physicochemical, quality and nutritional properties of Nigella sativa oil. Food Rev Int. 2019;35(4):342–62.

    CAS  Google Scholar 

  28. 28.

    Longato E, Meineri G, Peiretti PG. Nutritional and zootechnical aspects of Nigella sativa: a review. 2015.

  29. 29.

    Hadi MY, Mohammed GJ, Hameed IH. Analysis of bioactive chemical compounds of Nigella sativa using gas chromatography-mass spectrometry. J Pharmacogn Phytother. 2016;8(2):8–24.

    CAS  Google Scholar 

  30. 30.

    Karna S. Phytochemical screening and gas chromatography mass spectrometry and analysis of seed extract of Nigella sativa Linn. Int J Chem Studies. 2013;1(4):183–8.

    Google Scholar 

  31. 31.

    Aljabre SH, Alakloby OM, Randhawa MA. Dermatological effects of Nigella sativa. J Dermatol Dermatologic Surg. 2015;19(2):92–8.

    Google Scholar 

  32. 32.

    Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, Siddique NA, et al. A review on therapeutic potential of Nigella sativa: a miracle herb. Asian Pac J Trop Biomed. 2013;3(5):337–52.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Kilinc E, Dagistan Y, Kotan B, Cetinkaya A. Effects of Nigella sativa seeds and certain species of fungi extracts on number and activation of dural mast cells in rats. Physiology Int. 2017;104(1):15–24.

    CAS  Google Scholar 

  34. 34.

    Shanmugam MK, Arfuso F, Kumar AP, Wang L, Goh BC, Ahn KS, et al. Modulation of diverse oncogenic transcription factors by thymoquinone, an essential oil compound isolated from the seeds of Nigella sativa Linn. Pharmacol Res. 2018;129:357–64.

    CAS  PubMed  Google Scholar 

  35. 35.

    Hamed M, El-Rigal N, Ali S. Effects of black seed oil on resolution of hepato-renal toxicity induced by bromobenzene in rats. Eur Rev Med Pharmacol Sci. 2013;17(5):569–81.

    CAS  PubMed  Google Scholar 

  36. 36.

    Zaghlol DAA, Kamel ES, Mohammed DS, Abbas NH. The possible toxic effect of different doses of Nigella sativa oil on the histological structure of the liver and renal cortex of adult male albino rats. Egyptian J Histol. 2012;35(1):127–36.

    Google Scholar 

  37. 37.

    Chehl N, Chipitsyna G, Gong Q, Yeo CJ, Arafat HA. Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. Hpb. 2009;11(5):373–81.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Periasamy VS, Athinarayanan J, Alshatwi AA. Anticancer activity of an ultrasonic nanoemulsion formulation of Nigella sativa L. essential oil on human breast cancer cells. Ultrason Sonochem. 2016;31:449–55.

    CAS  PubMed  Google Scholar 

  39. 39.

    Faubert B, Vincent EE, Poffenberger MC, Jones RG. The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer Lett. 2015;356(2):165–70.

    CAS  PubMed  Google Scholar 

  40. 40.

    Zadra G, Batista JL, Loda M. Dissecting the dual role of AMPK in cancer: from experimental to human studies. Mol Cancer Res. 2015;13(7):1059–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Majdalawieh AF, Fayyad MW, Nasrallah GK. Anti-cancer properties and mechanisms of action of thymoquinone, the major active ingredient of Nigella sativa. Crit Rev Food Sci Nutr. 2017;57(18):3911–28.

    CAS  PubMed  Google Scholar 

  42. 42.

    Thirupathi A, Chang Y-Z. Role of AMPK and its molecular intermediates in subjugating cancer survival mechanism. Life Sci. 2019;227:30–8.

    CAS  PubMed  Google Scholar 

  43. 43.

    Cordero MD. Viollet B. AMP-activated protein kinase: Springer; 2016.

    Google Scholar 

  44. 44.

    Xin C, Liu J, Zhang J, Zhu D, Wang H, Xiong L, et al. Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway. Int J Obes. 2016;40(3):443–51.

    CAS  Google Scholar 

  45. 45.

    Meddah B, Ducroc R, Faouzi MEA, Eto B, Mahraoui L, Benhaddou-Andaloussi A, et al. Nigella sativa inhibits intestinal glucose absorption and improves glucose tolerance in rats. J Ethnopharmacol. 2009;121(3):419–24.

    PubMed  Google Scholar 

  46. 46.

    Liang Z, Li T, Jiang S, Xu J, Di W, Yang Z, et al. AMPK: a novel target for treating hepatic fibrosis. Oncotarget. 2017;8(37):62780–92.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Woods A, Williams JR, Muckett PJ, Mayer FV, Liljevald M, Bohlooly-Y M, et al. Liver-specific activation of AMPK prevents steatosis on a high-fructose diet. Cell Rep. 2017;18(13):3043–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Foretz M, Even PC, Viollet B. AMPK activation reduces hepatic lipid content by increasing fat oxidation in vivo. Int J Mol Sci. 2018;19(9):2826.

    PubMed Central  Google Scholar 

  49. 49.

    Motoshima H, Goldstein BJ, Igata M, Araki E. AMPK and cell proliferation–AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol. 2006;574(1):63–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Shirwany NA, Zou M-H. AMPK in cardiovascular health and disease. Acta Pharmacol Sin. 2010;31(9):1075–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Andersson LE, Shcherbina L, Al-Majdoub M, Vishnu N, Arroyo CB, Carrara JA, et al. Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase. Diabetes. 2018;67(3):372–84.

    CAS  PubMed  Google Scholar 

  52. 52.

    O'Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493(7432):346–55.

    CAS  PubMed  Google Scholar 

  53. 53.

    Tsoupras A, Lordan R, Zabetakis I. Inflammation, not cholesterol, is a cause of chronic disease. Nutrients. 2018;10(5):604.

    PubMed Central  Google Scholar 

  54. 54.

    Mancini SJ, Salt IP. Investigating the role of AMPK in inflammation. AMPK. Springer; 2018. p. 307–319.

  55. 55.

    Peixoto CA, de Oliveira WH, da Racho Araújo SM, Nunes AKS. AMPK activation: role in the signaling pathways of neuroinflammation and neurodegeneration. Exp Neurol. 2017;298:31–41.

    CAS  PubMed  Google Scholar 

  56. 56.

    Hardie DG. Molecular pathways: is AMPK a friend or a foe in cancer? Clin Cancer Res. 2015;21(17):3836–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Salt IP, Hardie DG. AMP-activated protein kinase: an ubiquitous signaling pathway with key roles in the cardiovascular system. Circ Res. 2017;120(11):1825–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Smith BK, Marcinko K, Desjardins EM, Lally JS, Ford RJ, Steinberg GR. Treatment of nonalcoholic fatty liver disease: role of AMPK. Am J Physiol-Endocrinol Metab. 2016;311(4):E730–E40.

    PubMed  Google Scholar 

Download references


The authors would like to thank the Nutrition Research Center of Tabriz University of Medical Sciences for their support.

Availability of data and materials

All data generated or analyzed are included in the results of the manuscript.

Author information




OT and VM contributed to search and data extraction. VM and JM contributed to data interpretation. MS, MA and ET contributed to manuscript drafting and data interpretation. All authors approved the final manuscript for submission.

Corresponding authors

Correspondence to Vahid Maleki or Mohammad Alizadeh.

Ethics declarations

Competing interests

All of the authors declared no personal or financial conflicts of interest.

Consent for publication

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tavakoli-Rouzbehani, O.M., Maleki, V., Shadnoush, M. et al. A comprehensive insight into potential roles of Nigella sativa on diseases by targeting AMP-activated protein kinase: a review. DARU J Pharm Sci 28, 779–787 (2020). https://doi.org/10.1007/s40199-020-00376-3

Download citation


  • Nigella sativa
  • AMP-activated protein kinase