Role of apigenin in targeting metabolic syndrome: A systematic review

Document Type : Review Article


Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran


Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that has a high prevalence worldwide. Apigenin is a flavonoid present in several vegetables and fruits and has anti-inflammatory, anti-oxidant, and anti-MetS properties. This study aims to systematically review the effects of apigenin against MetS and the relevant molecular and cellular mechanisms of action, pharmacokinetics features, and potential structure-activity relationship. Electronic databases including Scopus, PubMed, Science Direct and Cochrane Library were searched for in vivo, and in vitro, and human studies with the following keywords: “apigenin” and “metabolic syndrome or insulin resistance syndrome”, “fatty liver”, “hypertension or blood pressure”, “diabetes or blood glucose”, “dyslipidemia”, “heart or cardiovascular ” and “obesity” in title/abstract. Data were collected from 2000 until 2021 (up to April). Only papers published in the English language were included. Forty-six full-text articles out of 1016 retrieved papers were reviewed and underwent quality assessment by investigators. Anti-obesity activity of apigenin is mainly through attenuating adipocyte differentiation by suppressing the mitotic clonal expansion and the adipogenesis-related factors. Its anti-diabetic effects can be exerted through inhibition of protein tyrosine phosphatase1B expression, maintaining the activity of anti-oxidant enzymes, reducing intracellular ROS production, cellular DNA damage, protein carbonylation, and attenuating β-cell apoptosis. Moreover, apigenin could attenuate dyslipidemia and subsequent atherosclerotic conditions through down-regulating sterol regulatory element-binding proteins (SREBP)-1c, SREBP-2, stearyl-CoA desaturase-1, and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Apigenin as a dietary bioactive compound would be a promising candidate for improving MetS and its components.


Main Subjects

1.    Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep 2018; 20:1-8.
2.    McCracken E, Monaghan M, Sreenivasan S. Pathophysiology of the metabolic syndrome. Clin Dermatol 2018; 36: 14-20.
3.    Engin A. The definition and prevalence of obesity and metabolic syndrome. Ad Exp Med Biol  2017; 960: 1-17.
4.    Rochlani Y, Pothineni V, Kovelamudi S, Mehta JL. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther Adv Cardiovasc Dis 2017; 11:215-225.
5.    Hopps E, Noto D, Caimi G, Averna M. A novel component of the metabolic syndrome: the oxidative stress. Nutr Metab Cardiovasc Dis 2010; 20: 72-77.
6.    Khaafi M, Tayarani-Najaran Z, Javadi B. Cinnamaldehyde as a promising dietary phytochemical against metabolic syndrome: A systematic review. Mini Rev Med Chem 2023; 24: 355-369.    Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol  2013; 3: 1-58.
8.    Kim B, Feldman EL. Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome. Exp Mol Med 2015; 47:e149.
9.    Grundy SM. Metabolic syndrome update. Trends Cardiovasc Med 2016; 26: 364-373.
10. Rao T, Tan Z, Peng J, Guo Y, Chen Y, Zhou H, et al. The pharmacogenetics of natural products: a pharmacokinetic and pharmacodynamic perspective. Pharmacol Res 2019; 146: 104283.
11. Javadi B, Sahebkar A, Emami SA. Medicinal plants for the treatment of asthma: A traditional Persian medicine perspective. Curr Pharm Des 2017; 23: 1623-1632.
12. Highlights of prescribing information  [Available from:
13. Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020;83:770-803.
14. Ren N, Kim E, Li B, Pan H, Tong T, Yang CS, et al. Flavonoids alleviating insulin resistance through inhibition of inflammatory signaling. J Agric Food Chem 2019; 67:5361-5373.
15. Russo B, Picconi F, Malandrucco I, Frontoni S. Flavonoids and insulin-resistance: from molecular evidences to clinical trials. Int J Mol Sci 2019;  20:2061-2078.
16. Madunić J, Madunić IV, Gajski G, Popić J, Garaj-Vrhovac V. Apigenin: A dietary flavonoid with diverse anticancer properties. Cancer Lett 2018; 413: 11-22.
17. Tang D, Chen K, Huang L, Li J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opin Drug Metab Toxicol 2017; 13: 323-330.
18. Zhang J, Liu D, Huang Y, Gao Y, Qian S. Biopharmaceutics classification and intestinal absorption study of apigenin. Int J Pharm 2012; 436: 311-317.
19. Ono M, Fujimori K. Antiadipogenic effect of dietary apigenin through activation of AMPK in 3T3-L1 cells. J Agric Food Chem  2011; 59: 13346-13352.
20. Jung UJ, Cho YY, Choi MS. Apigenin ameliorates dyslipidemia, hepatic steatosis and insulin resistance by modulating metabolic and transcriptional profiles in the liver of high-fat diet-induced obese mice. Nutrients 2016; 8: 305-320.
21. Yang M, Jiang  Zh, Li C,  Zhu YJ, Li  Z, Tang YZ, et al. Apigenin prevents metabolic syndrome in high-fructose diet-fed mice by Keap1-Nrf2 pathway. Biomed Pharmacother 2018; 105:1283-1290.
22. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. J Pharmacol Pharmacother 2010; 1: 94–99.
23. Ulrey A, Kolle S, Landsiedel R, Hill E. How a GIVIMP certification program can increase confidence in in vitro methods. ALTEX 2021; 38: 316-318. 
24. Zafar U, Khaliq S, Ahmad H.U, Manzoor S, Lone K.P. Metabolic syndrome: an update on diagnostic criteria, pathogenesis, and genetic links. Hormones 2018; 17: 299-313.
25. Myers J, Kokkinos P, Nyelin E. Physical activity, cardiorespiratory fitness, and the metabolic syndrome. Nutrients 2019; 11: 1652. 
26. Maslov L.N, Naryzhnaya N.V, Boshchenko A.A, Popov S.V, Ivanov V.V, Oeltgen P.R. Is oxidative stress of adipocytes a cause or a consequence of the metabolic syndrome? J Clin Transl Endocrinol 2019; 15:1-5.
27. Reddy P, Lent-Schochet D, Ramakrishnan N, McLaughlin M, Jialal I. Metabolic syndrome is an inflammatory disorder: A conspiracy between adipose tissue and phagocytes. Clinica Chimica Acta 2019;496: 35-44.
28. Festa A, D’Agostino R Jr, Howard G, Mykkanen, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: The insulin resistance atherosclerosis study (IRAS). Circulation 2000; 102: 42-47. 
29. Kim MA, Kang K, Lee HJ, Kim M, Kim CY, Nho CW. Apigenin isolated from Daphne genkwa Siebold et Zucc. inhibits 3T3-L1 preadipocyte differentiation through a modulation of mitotic clonal expansion. Life Sci 2014;101: 64-72.
30. Hong YN, Chun J, Kim YS. Anti-adipogenic activity of Carduus crispus and its constituent apigenin in 3T3-L1 adipocytes by down-regulating PPARγ and C/EBPα. Eur Food Res. Technol 2016; 242: 1555-1563.
31. Guo X, Liu J, Cai S, Wang O, Ji B. Synergistic interactions of apigenin, naringin, quercetin and emodin on inhibition of 3T3-L1 preadipocyte differentiation and pancreas lipase activity. Obes Res Clin Pract 2016; 10: 327-339.
32. Feng X, Weng D,  Zhou F, Owen YD, Qin H,  Zhao J, et al. Activation of PPARγ by a natural flavonoid modulator, apigenin ameliorates obesity-related inflammation via regulation of macrophage polarization. EBio Medicine 2016; 9: 61-76.
33. Gentile D, Fornai M, Colucci R, Pellegrini C, Tirotta E, Benvenuti L, et al. The flavonoid compound apigenin prevents colonic inflammation and motor dysfunctions associated with high fat diet-induced obesity. PLoS One 2018; 13:e0195502.
34. Escande C, Nin V, Price NL, Capellini V, Gomes AP, Barbosa MT, et al. Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes Metab Syndr Obes: Targets Ther 2013; 62: 1084-1093.
35. Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P. Metabolic adaptations through the PGC-1α and SIRT1 pathways. FEBS Lett 2008; 582: 46-53.
36. Sun YS, Qu W. Dietary Apigenin promotes lipid catabolism, thermogenesis, and browning in AT of HFD-Fed mice. Food Chem Toxicol 2019;133: 110780.
37. Okla M, Al Madani JO, Chung S, Alfayez M. Apigenin reverses interleukin‐1β‐induced suppression of adipocyte browning via cox2/pge2 signaling pathway in human adipocytes. Mol Nutr Food Res 2020; 64:1900925.
38. Aranaz P, Navarro-Herrera D, Zabala M, Romo-Hualde A, López-Yoldi M, Vizmanos JL, et al. Phenolic compounds reduce the fat content in caenorhabditis elegans by affecting lipogenesis, lipolysis, and different stress responses. Pharmaceuticals (Basel) 2020; 13:355-387.
39. Su T, Huang C,  Yang C,  Jiang T,  Su J, Chen M, et al. Apigenin inhibits STAT3/CD36 signaling axis and reduces visceral obesity. Pharmacol Res 2020; 152: 104586.
40. Wu L, Guo T, Deng R, Liu L, Yu Y. Apigenin ameliorates insulin resistance and lipid accumulation by endoplasmic reticulum stress and SREBP-1c/SREBP-2 pathway in palmitate-induced HepG2 Cells and high-fat diet–fed mice. J Pharmacol Exp Ther 2021; 377: 146-156.
41. Meshkani R, Adeli K. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clin Biochem 2009; 42: 1331-1346.
42. Ali MY, Jannat S, Rahman MM. Investigation of C-glycosylated apigenin and luteolin derivatives’ effects on protein tyrosine phosphatase 1B inhibition with molecular and cellular approaches. Comput Toxicol 2021; 17: 100141.
43. Cho H. Protein tyrosine phosphatase 1B (PTP1B) and obesity. Vitam Horm 2013; 91: 405-424.
44. Panda S, Kar A. Apigenin (4 ‘, 5, 7‐trihydroxyflavone) regulates hyperglycaemia, thyroid dysfunction and lipid peroxidation in alloxan‐induced diabetic mice. J Pharm Pharmacol 2007; 59: 1543-1548.
45. Rauter AP, Martins A, Borges C, Mota‐Filipe H, Pinto R, Sepodes B, Justino J. Antihyperglycaemic and protective effects of flavonoids on streptozotocin–induced diabetic rats. Phytother Res 2010; 24 Suppl 2:S133-S138. 
46. Esmaeili MA, Zohari F, Sadeghi H. Anti-oxidant and protective effects of major flavonoids from teucrium polium on β-cell destruction in a model of streptozotocin-induced diabetes. Planta Med 2009; 75: 1418-1420.
47. Wang N, Yi WJ, Tan L,  Zhang JH,  Xu J, Chen Y, et al. Apigenin attenuates streptozotocin-induced pancreatic β cell damage by its protective effects on cellular antioxidant defense. In vitro Cell Dev Biol Anim  2017; 53: 554-563.
48. Suh KS, Oh S, Woo JT, Kim SW, Kim JW, Kim YS, et al. Apigenin attenuates 2-deoxy-D-ribose-induced oxidative cell damage in HIT-T15 pancreatic β-cells. Biol Pharm Bull 2012; 35: 121-126.
49. Fan JF, Johnson MH,  Lila MA,  Yousef G, de Mejia EG. Berry and citrus phenolic compounds inhibit dipeptidyl peptidase IV: Implications in diabetes management. Evid Based Complement Alternat Med 2013; 3:479505.
50. Bumke-Vogt C,  Osterhoff MA, Borchert A, Guzman-Perez V, Sarem Z, Birkenfeld AL, et al. The flavones apigenin and luteolin induce FOXO1 translocation but inhibit gluconeogenic and lipogenic gene expression in human cells. PLoS One 2014; 9:e104321. 
51. Hossain CM, Ghosh MK, Satapathy BS, Dey NS, Mukherjee B. Apigenin causes biochemical modulation, GLUT4 and CD38 alterations to improve diabetes and to protect damages of some vital organs in experimental diabetes. Am J Pharmacol Toxicol 2014; 9: 39-52.
52. Li K, Yao F, Xue Q, Fan H, Yang L, Li X, Sun L, Liu Y. Inhibitory effects against α-glucosidase and α-amylase of the flavonoids-rich extract from Scutellaria baicalensis shoots and interpretation of structure–activity relationship of its eight flavonoids by a refined assign-score method. Chem Cent J 2018; 12: 1-11.
53. Dostálek P, Karabín M, Jelínek L. Hop phytochemicals and their potential role in metabolic syndrome prevention and therapy. Molecules 2017; 22: 1761-1771.
54. Fujii N, Narita T,  Okita N, Kobayashi M, Furuta Y, Chujo Y,  et al. Sterol regulatory element‐binding protein‐1c orchestrates metabolic remodeling of white AT by caloric restriction. Aging Cell 2017;16: 508-517.
55. Kim KT, Yeo EJ,  Moon SH,  Cho SG, Han YS,  Nah SY, et al. Inhibitory effects of naringenin, kaempherol, and apigenin on cholesterol biosynthesis in HepG2 and MCF-7 cells Food Sci Biotechnol. 2008; 17: 1361-1364.
56. Zhang K, Song W, Li D,  Jin X. Apigenin in the regulation of cholesterol metabolism and protection of blood vessels. Exp Ther Med 2017; 13: 1719-1724.
57. Wang N, Westerterp M. ABC transporters, cholesterol efflux, and implications for cardiovascular diseases. lipid transfer in lipoprotein metabolism and cardiovascular disease. Adv Exp Med Biol 2020:1276:67-83.
58. Ren K, Jiang T,  Zhou HF, Liang Y,  Zhao GJJ. Apigenin retards atherogenesis by promoting ABCA1-mediated cholesterol efflux and suppressing inflammation. Cell Physiol Biochem 2018; 47: 2170-2184.
59. Chen L, Zheng L, Chen P, Liang G. Myeloid differentiation primary response protein 88 (MyD88): The central hub of TLR/IL-1R signaling. J Med Chem 2020; 63: 13316-13329.
60. Wong TY, Tan YQ,  Lin SM,  Leung LK. Apigenin and luteolin display differential hypocholesterolemic mechanisms in mice fed a high-fat diet. Biomed Pharmacother 2017; 96:1000-1007.
61. Wong TY, Tan YQ, Lin SM,  Leung LKJ. Co-administrating apigenin in a high-cholesterol diet prevents hypercholesterolaemia in golden hamsters. J Pharm Pharmacol  2018; 70: 1253-1261.
62. Feng X, Yu W,  Li X,  Zhou F,  Zhang W,  Shen Q, et al. Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation. Biochem Pharmacol  2017;136:136-149.
63. Wang F, Liu JC, Zhou RJ, Zhao X, Liu M, Ye H, Xie Me-Li. Apigenin protects against alcohol-induced liver injury in mice by regulating hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression. Chem Biol Interact 2017; 275: 171-177.
64. Lv Y, Gao X, Luo Y, Fan W, Shen T, Ding C, et al. Apigenin ameliorates HFD-induced NAFLD through regulation of the XO/NLRP3 pathways 2019; 71: 110-121.
65. Yue S, Xue N,  Li H,  Huang B, Chen  Z, Wang XJ. Hepatoprotective effect of apigenin against liver injury via the non-canonical NF-κB pathway in vivo and in vitro. Inflammation 2020; 43: 1634-1648.
66. Sui H, Yan W, Geng G. Effect of apigenin on SBP of spontaneous hypertension rats and its mechanism. J Environ Health 2009; 26: 112-113.
67. Zhu ZY, Gao T,  Huang Y,  Xue J,  Xie ML. Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats. Food Func 2016; 7: 1992-1998.
68. Zhang YH, Park YS,  Kim TJ,  Fang LH, Ahn HY,  Hong JT, et al. Endothelium-dependent vasorelaxant and antiproliferative effects of apigenin. Gen Pharmacol:the Vascular System 2000; 35: 341-347.
69. Jing Y,  Chen R, Dong M,  Liu Y,  Hou X,  Guo P,  et al. Apigenin relaxes rat intrarenal arteries, depresses Ca(2+)-activated Cl(-) currents and augments voltage-dependent K(+) currents  of the arterial smooth muscle cells. Biomed Pharmacother 2019; 115:  108926.
70. Qin W, Ren B,  Wang S,  Liang  S,  He B,  Shi X,  et al. Apigenin and naringenin ameliorate PKCβII-associated endothelial dysfunction via regulating ROS/caspase-3 and NO pathway in endothelial cells exposed to high glucose. Vascul Pharmacol 2016; 85: 39-49.
71. Sukandar EY, Ridwan A, Sukmawan YP. Vasodilation effect of oleanolic acid and apigenin as a metabolite compound of Anredera cordifolia (Ten) V Steenis on isolated rabbit aortic and frog heart. Int J Res Ayurveda Pharm 2016; 7: 82-84.
72. Loizzo MR, Said A, Tundis R, Rashed K, Statti GA, Hufner A, et al. Inhibition of angiotensin converting enzyme (ACE) by flavonoids isolated from Ailanthus excelsa (Roxb)(Simaroubaceae) Phytother Res 2007; 21:32-36.
73. Paredes MD, Romecín P, Atucha NM, O’Valle F, Castillo J,  Ortiz MC, et al. Beneficial effects of different flavonoids on vascular and renal function in L-NAME hypertensive rats. Nutrients 2018; 10:484-498.
74. Buwa CC, Mahajan UB, Patil CR, Goyal SN. Apigenin attenuates β-receptor-stimulated myocardial injury via safeguarding cardiac functions and escalation of anti-oxidant defence system. Cardiovasc Toxicol 2016; 16: 286-297.
75. Zeng P, Liu B,  Wang Q, Fan Q, Diao JX, Tang J, et al. Apigenin attenuates atherogenesis through inducing macrophage apoptosis via inhibition of AKT Ser473 phosphorylation and down-regulation of plasminogen activator inhibitor-2. Oxid Med Cell Longev 2015; 2015:379538. 
76. Clayton ZS, Hutton DA, Brunt VE, VanDongen NS, Ziemba BP, Casso AG, et al. Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging. Am J PhysiolHeart Circ Physiol 2021; 321:H185-H196.
77. Gao HL, Yu XJ,  Hu HB, Yang QW,  Liu KL,  Chen YM,  et al. Apigenin improves hypertension and cardiac hypertrophy through modulating NADPH oxidase-dependent ROS generation and cytokines in hypothalamic paraventricular nucleus. Cardiovasc Toxicol  2021; 9: 721-736.
78. Zhang P,  Mak JC,  Man RY,  Leung SW. Flavonoids reduces lipopolysaccharide-induced release of inflammatory mediators in human bronchial epithelial cells: Structure-activity relationship. Eur J Pharmacol 2019; 865: 172731.
79. Loizzo M,  Lecce GD, Boselli E, Menichini F, Frega N. Inhibitory activity of phenolic compounds from extra virgin olive oils on the enzymes involved in diabetes, obesity and hypertension. J Food Biochem 2011; 35: 381-399.
80. He Y,  Xia Z,  Yu D,  Wang J,  Jin L, Huang D, et al. Hepatoprotective effects and structure-activity relationship of five flavonoids against lipopolysaccharide/d-galactosamine induced acute liver failure in mice. Int Immunopharmacol 2019; 68:171-178.
81. Ding Sm, Zhang Zh, Song J, Cheng Xd,  Jiang J,  Jia Xb. Enhanced bioavailability of apigenin via preparation of a carbon nanopowder solid dispersion. Int J Nanomedicine 2014; 9: 2327-2333.
82. DeRango-Adem EF, Blay J. Does oral apigenin have real potential for a therapeutic effect in the context of human gastrointestinal and other cancers? Front Pharmacol 2021; 12, 681477.
83. Wan L, Guo C, Yu Q, Li Y, Wang Xia, Wang Xiao, et al. Quantitative determination of apigenin and its metabolism in rat plasma after intravenous bolus administration by HPLC coupled with tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2007; 855:286-289.
84. Gradolatto A, Basly JP,  Berges R,  Teyssier C,  Chagnon MC,  Siess MH, et al. Pharmacokinetics and metabolism of apigenin in female and male rats after a single oral administration. Drug Metab Dispos 2005; 33:49-54.
85. Tang L, Zhou J, Yang CH, Xia BJ, Hu M, Liu ZQ. Systematic studies of sulfation and glucuronidation of 12 flavonoids in the mouse liver S9 fraction reveal both unique and shared positional preferences. J Agric Food Chem 2012; 60:3223-3233.
86. Sen K, Banerjee S, Mandal M. Dual drug loaded liposome bearing apigenin and 5-Fluorouracil for synergistic therapeutic efficacy in colorectal cancer. Colloids Surf B 2019;180:9-22.