Exploring the Hepatoprotective Effects of Naringin: A Systematic Review and Meta-Analysis of Preclinical Evidence

Abstract

This study aimed to perform a systematic review and meta-analysis on the hepatoprotective effects of naringin based on the pre-clinical evidence.

A detailed literature search was performed using online databases such as Google Scholar, PubMed, Scopus, and EMBASE. Based on the predefined inclusion and exclusion criteria, 20 studies were considered for meta-analysis.

The outcomes of the meta-analysis revealed that naringin improved liver function by reducing the elevated levels of ALT, AST, GGT, LDH, ALP, and bilirubin. It improved the enzymatic and non-enzymatic antioxidants, such as SOD, catalase, GSH, GST, GR, and GPx (p < 0.05 for all the parameters), while reducing the LPO/MDA levels (p < 0.05). NAR treatment also alleviated the levels of inflammatory mediators (IL-1β, IL-6, and TNF-α, p < 0.001 for all the parameters; NF-κB, p = 0.29) in various animal models of liver injury. In addition, NAR significantly reduced the caspase-3 and Bax/Bcl-2 ratio (p < 0.05) compared to the control group. Furthermore, naringin treatment has normalised the liver and body weights compared to the disease control group.

This systematic review and meta-analysis demonstrate that naringin significantly improved the liver function in various animal models of liver injury, via potent antioxidant and anti-inflammatory mechanisms.

Keywords

naringin - hepatoprotection - antioxidant - anti-inflammatory - hepatotoxicity

Publication History

Received: 02 January 2025

Accepted after revision: 23 April 2025

Article published online:
14 May 2025

• References

• 1 Trefts E, Gannon M, Wasserman DH. The liver. Curr Biol 2017; 27: R1147-R1151
• 2 Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol 2019; 70: 151-171
• 3 Cheemerla S, Balakrishnan M. Global epidemiology of chronic liver disease. Clin Liver Dis (Hoboken) 2021; 17: 365-370
• 4 Viswanatha GL, Shylaja H, Moolemath Y. The beneficial role of Naringin- a citrus bioflavonoid, against oxidative stress-induced neurobehavioral disorders and cognitive dysfunction in rodents: A systematic review and meta-analysis. Biomed Pharmacother 2017; 94: 909-929
• 5 Stabrauskiene J, Kopustinskiene DM, Lazauskas R, Bernatoniene J. Naringin and naringenin: Their mechanisms of action and the potential anticancer activities. Biomedicines 2022; 10: 1686
• 6 Viswanatha GL, Shylaja H, Keni R, Nandakumar K, Rajesh S. A systematic review and meta-analysis on the cardio-protective activity of naringin based on pre-clinical evidences. Phytother Res 2022; 36: 1064-1092
• 7 Alam MA, Subhan N, Rahman MM, Uddin SJ, Reza HM, Sarker SD. Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action. Adv Nutr 2014; 5: 404-417
• 8 Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 2015; 16: 26087-26124
• 9 Ahn E, Kang H. Introduction to systematic review and meta-analysis. Korean J Anesthesiol 2018; 71: 103-112
• 10 Esuola LO, Esan O, Maikifi AS, Ajibade TO, Adetona MO, Oyagbemi AA, Omobowale TO, Oladele OA, Oguntibeju OO, Nwulia E, Yakubu MA. Bisphenol A toxicity induced hepatotoxicity and altered biochemical, histopathology, and immunohistochemical parameters: The metal chelating and antioxidant roles of naringin. Comp Clin Path 2023; 32: 993-1004
• 11 Pari L, Amudha K. Hepatoprotective role of naringin on nickel-induced toxicity in male Wistar rats. Eur J Pharmacol 2011; 650: 364-370
• 12 Akamo AJ, Rotimi SO, Akinloye DI, Ugbaja RN, Adeleye OO, Dosumu OA, Eteng OE, Amah G, Obijeku A, Cole OE. Naringin prevents cyclophosphamide-induced hepatotoxicity in rats by attenuating oxidative stress, fibrosis, and inflammation. Food Chem Toxicol 2021; 153: 112266
• 13 Marzook Abdelmageed E, Abdel-Aziz AF, Abd El-Moneim AE, Mansour HA, Atia KS, Salah NA. MicroRNA-122 expression in hepatotoxic and γ-irradiated rats pre-treated with naringin and silymarin. J Radiat Res Appl Sci 2020; 13: 38-46
• 14 Khaled SS, Soliman HA, Abdel-Gabbar M, Ahmed NA, El-Nahass ES, Ahmed OM. Naringin and naringenin counteract taxol-induced liver injury in Wistar rats via suppression of oxidative stress, apoptosis and inflammation. Environ Sci Pollut Res Int 2023; 30: 90892-90905
• 15 Ali Ali L, Prem K, Rizwan NU, Mohamed AN. Pyrethroid deltamethrin induced haematological and hepato-pathological impairment in male Wistar rats and potential attenuation by flavonoid naringin. Int J Sci Humanit 2015; 1: 623-640
• 16 Ahmed OM, Fahim HI, Ahmed HY, Al-Muzafar HM, Ahmed RR, Amin KA, Ell-Nahas E, Abdelazeem WH. The preventive effects and the mechanisms of action of navel orange peel hydroethanolic extract, naringin, and naringenin in N-Acetyl-p-aminophenol-induced liver injury in wistar rats. Oxid Med Cell Longev 2019; 2019: 2745352
• 17 Ali Ali L, Magendira Mani V, Gokulakrishnan A, Alagesan D, Professor A. Protective Effect of Flavonoid Naringin on Lambda cyhalothrin Induced Haematological and Hepato-Pathological Variations in Male Wistar Rats. Hem Dis Ther 2017; 1-9
• 18 Hemaid Abd El-Makesoud N, Saber Ibrahim S, Mohammed Said A. Potential hepato-protective effect of naringin and propolis against furan toxicity: A Comparative study. Benha Vet Med J 2022; 43: 15-18
• 19 Hassan RA, Hozayen WG, Abo Sree HT, Al-Muzafar HM, Amin KA, Ahmed OM. Naringin and hesperidin counteract diclofenac-induced hepatotoxicity in male wistar rats via their antioxidant, anti-inflammatory, and antiapoptotic activities. Oxid Med Cell Longev 2021; 2021: 9990091
• 20 Lin Z, Wang G, Gu W, Zhao S, Shen Z, Liu W, Zheng G, Chen B, Cai Y, Li M, Wan CC, Yan T. Exploration of the protective mechanism of naringin in the acetaminophen-induced hepatic injury by metabolomics. Oxid Med Cell Longev 2022; 2022: 7138194
• 21 Adil M, Kandhare AD, Ghosh P, Venkata S, Raygude KS, Bodhankar SL. Ameliorative effect of naringin in acetaminophen-induced hepatic and renal toxicity in laboratory rats: Role of FXR and KIM-1. Ren Fail 2016; 38: 1007-1020
• 22 Anis A, El-Nady SH, Amer HA, Borai El-Borai N, El-Ballal SS. Journal of current veterinary research ameliorative potential of naringin against Di–n-butyl phthalate-induced hepatorenal toxicity in rats. J Curr Vet Res 2023; 5: 17-32
• 23 Gelen V, Şengül E, Yıldırım S, Atila G. The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. Iran J Basic Med Sci 2018; 21: 404-410
• 24 Mahdavinia M, Khorsandi L, Alboghobeish S, Samimi A, Dehghani MA, Zeidooni L. Liver histopathological alteration and dysfunction after bisphenol A administration in male rats and protective effects of naringin. Avicenna J Phytomed 2021; 11: 394-406
• 25 Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res Int 2018; 25: 20968-20984
• 26 Rodríguez V, Plavnik L, Tolosa de Talamoni N. Naringin attenuates liver damage in streptozotocin-induced diabetic rats. Biomed Pharmacother 2018; 105: 95-102
• 27 Xi Y, Chi Z, Tao X, Zhai X, Zhao Z, Ren J, Yang S, Dong D. Naringin against doxorubicin-induced hepatotoxicity in mice through reducing oxidative stress, inflammation, and apoptosis via the up-regulation of SIRT1. Environ Toxicol 2023; 38: 1153-1161
• 28 Badr HM, Ashour AM, El-Kott AF. Hepatoprotective activity of of naringin against acute hepatotoxicity in rats. Con Basic Sci 2009; 1-10
• 29 El-Mihi KA, Kenawy HI, El-Karef A, Elsherbiny NM, Eissa LA. Naringin attenuates thioacetamide-induced liver fibrosis in rats through modulation of the PI3K/Akt pathway. Life Sci 2017; 187: 50-57
• 30 Impellizzeri FM, Bizzini M. Systematic review and meta‐analysis: A primer. Int J Sports Phys Ther 2012; 7: 493
• 31 Testing.com. Alanine Aminotransferase (ALT). Accessed April 22, 2024 at: https://www.testing.com/tests/alanine-aminotransferase-alt/
• 32 Cleveland Clinic. Alanine Transaminase (ALT) Blood Test: What It Is, Procedure & Results. Accessed April 22, 2024 at: https://my.clevelandclinic.org/health/diagnostics/22028-alanine-transaminase-alt
• 33 Cleveland Clinic. Gamma-Glutamyl Transferase (GGT) Test: What It Is & Results. Accessed April 22, 2024 at: https://my.clevelandclinic.org/health/diagnostics/22055-gamma-glutamyl-transferase-ggt-test
• 34 Kotoh K, Kato M, Kohjima M, Tanaka M, Miyazaki M, Nakamura K. Lactate dehydrogenase production in hepatocytes is increased at an early stage of acute liver failure. Exp Ther Med 2011; 2: 195
• 35 Vuppalanchi R, Chalasani N. Laboratory Tests in Liver Disease. In: Romil Saxena. ed. Practical Hepatic Pathology: a Diagnostic Approach. New Delhi: Elsevier Publishers; 2011: 55-62
• 36 Ge P, Yang H, Lu J, Liao W, Du S, Xu Y, Xu H, Zhao H, Lu X, Sang X, Zhong S, Huang J, Mao Y. Albumin binding function: The potential earliest indicator for liver function damage. Gastroenterol Res Pract 2016; 2016: 5120760
• 37 Sun L, Yin H, Liu M, Xu G, Zhou X, Ge P, Yang H, Mao Y. Impaired albumin function: A novel potential indicator for liver function damage?. Ann Med 2019; 51: 333-344
• 38 Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med 2001; 30: 433-446
• 39 Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci 2008; 4: 89
• 40 Forman HJ, Zhang H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nat Rev Drug Discov 2021; 20: 689-709
• 41 Jena AB, Samal RR, Bhol NK, Duttaroy AK. Cellular Red-Ox system in health and disease: The latest update. Biomed Pharmacother 2023; 162: 114606
• 42 Ghadir MR, Riahin AA, Havaspour A, Nooranipour M, Habibinejad AA. The relationship between lipid profile and severity of liver damage in cirrhotic patients – PMC. Hepat Mon 2010; 10: 285-288
• 43 Honmore V, Kandhare A, Zanwar AA, Rojatkar S, Bodhankar S, Natu A. Artemisia pallens alleviates acetaminophen induced toxicity via modulation of endogenous biomarkers. Pharm Biol 2015; 53: 571-581
• 44 Ghadir MR, Riahin AA, Havaspour A, Nooranipour M, Habibinejad AA. The relationship between lipid profile and severity of liver damage in cirrhotic patients. Hepat Mon 2010; 10: 285
• 45 Wang P, Wang Y, Liu H, Han X, Yi Y, Wang X, Li X. Role of triglycerides as a predictor of autoimmune hepatitis with cirrhosis. Lipids Health Dis 2022; 21: 1-10
• 46 Tomizawa M, Kawanabe Y, Shinozaki F, Sato S, Motoyoshi Y, Sugiyama T, Yamamoto S, Sueishi M. Triglyceride is strongly associated with nonalcoholic fatty liver disease among markers of hyperlipidemia and diabetes. Biomed Rep 2014; 2: 633-636
• 47 Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RM, Weinberger C. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 1995; 81: 687-693
• 48 Fiorucci S, Rizzo G, Donini A, Distrutti E, Santucci L. Targeting farnesoid X receptor for liver and metabolic disorders. Trends Mol Med 2007; 13: 298-309
• 49 Chen WD, Wang YD, Meng Z, Zhang L, Huang W. Nuclear bile acid receptor FXR in the hepatic regeneration. Biochim Biophys Acta 2011; 1812: 888-892
• 50 Wagner M, Zollner G, Trauner M. Nuclear receptors in liver disease. Hepatology 2011; 53: 1023-1034
• 51 Tsamandas AC, Thomopoulos K, Zolota V, Kourelis T, Karatzas T, Ravazoula P, Tepetes K, Petsas T, Karavias D, Karatza C, Bonikos DS, Gogos C. Potential role of Bcl-2 and Bax mRNA and protein expression in chronic hepatitis type B and C: A clinicopathologic study. Mod Pathol 2003; 16: 1273-1288
• 52 Shang N, Bank T, Ding X, Breslin P, Li J, Shi B, Qiu W. Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p 38 activation. Cell Death Dis 2018; 9: 1-11
• 53 Thapaliya S, Wree A, Povero D, Inzaugarat ME, Berk M, Dixon L, Papouchado BG, Feldstein AE. Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet-induced NASH model. Dig Dis Sci 2014; 59: 1197-1206
• 54 Hammad M, Raftari M, Cesário R, Salma R, Godoy P, Emami SN, Haghdoost S. Roles of oxidative stress and Nrf2 signaling in pathogenic and non-pathogenic cells: A possible general mechanism of resistance to therapy. Antioxidants (Basel) 2023; 12: 1371
• 55 Ngo V, Duennwald ML. Nrf2 and oxidative stress: A general overview of mechanisms and implications in human disease. Antioxidants (Basel) 2022; 11: 2345
• 56 Ulasov AV, Rosenkranz AA, Georgiev GP, Sobolev AS. Nrf2/Keap1/ARE signaling: Towards specific regulation. Life Sci 2022; 291: 120111
• 57 Netea MG, Balkwill F, Chonchol M, Cominelli F, Donath MY, Giamarellos-Bourboulis EJ, Golenbock D, Gresnigt MS, Heneka MT, Hoffman HM, Hotchkiss R. A guiding map for inflammation. Nat Immunol 2017; 18: 826-831
• 58 Barbier L, Ferhat M, Salamé E, Robin A, Herbelin A, Gombert JM, Silvain C, Barbarin A. Interleukin-1 family cytokines: Keystones in liver inflammatory diseases. Front Immunol 2019; 10: 2014
• 59 Tak PP, Firestein GS. NF-κB: A key role in inflammatory diseases. J Clin Invest 2001; 107: 7-11
• 60 Niederreiter L, Tilg H. Cytokines and fatty liver diseases. Liver Res 2018; 2: 14-20
• 61 Shamsan E, Almezgagi M, Gamah M, Khan N, Qasem A, Chuanchuan L, Haining F. The role of PI3 k/AKT signaling pathway in attenuating liver fibrosis: A comprehensive review. Front Med (Lausanne) 2024; 11: 1389329
• 62 Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: From physiology to therapeutics. Signal Transduct Target Ther 2025; 10: 63