All Issue

2026 Vol.2, Issue 2 Preview Page

Review Article

Antiproliferative effects and preclinical limitations of quercetin in hepatocellular carcinoma
Ji-Yeon Mo1
,
Ho-Jun Lee1*
1R&B Research Institute, Cheonan 31007, Republic of Korea
*Corresponding Author
30 June 2026. pp. 123-132
PDF XML Citation
Abstract

Hepatocellular carcinoma (HCC) remains a major clinical burden because tumor heterogeneity, underlying liver dysfunction, recurrence, and variable therapeutic responses continue to limit durable disease control. Quercetin, a dietary flavonol, has been repeatedly investigated in HCC-related experimental systems, but its interpretation requires caution because most evidence remains preclinical and model-dependent. This review reinterprets quercetin-associated HCC evidence around a central mechanistic axis: redox regulation, p53/BAX-caspase-dependent apoptosis, survival signaling suppression, cell-cycle control, and lipid metabolic vulnerability. In HepG2-centered studies, quercetin reduced proliferation and induced apoptosis under time- and dose-dependent conditions, with reported changes in intracellular reactive oxygen species, caspase-3/9 activation, PI3K/Akt and ERK signaling, cyclin-related cell-cycle regulation, and fatty acid synthase activity. Comparative data, however, indicate that HCC cell lines do not respond uniformly; the limited response of Huh7 cells and the hepatoblastoma-derived origin of HepG2 restrict broad generalization to human HCC. Combination studies with cisplatin or 5-fluorouracil suggest experimental chemosensitization, not established clinical combination therapy. In vivo data from HepG2 xenografts support tumor-growth delay, but do not resolve pharmacokinetic, immune microenvironment, toxicity, and bioavailability limitations. Overall, quercetin is best interpreted as a multi-target preclinical candidate that may expose redox and metabolic vulnerabilities in selected HCC models, rather than as a validated HCC treatment.

Keywords
Apoptosis
Bioavailability
Hepatocellular carcinoma
Quercetin
Reactive oxygen species
References
1

Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. 2024. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74(3):229-263. https://doi.org/10.3322/caac.21834

10.3322/caac.21834
2

Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. 2021. Hepatocellular carcinoma. Nat Rev Dis Primers 7(1):6. https://doi.org/10.1038/s41572-020-00240-3

10.1038/s41572-020-00240-3
3

Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, Jou JH, Kulik LM, Agopian VG, Marrero JA, Mendiratta-Lala M, Brown DB, Rilling WS, Goyal L, Wei AC, Taddei TH. 2023. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 78(6):1922-1965. https://doi.org/10.1097/HEP.0000000000000466

10.1097/HEP.000000000000046637199193PMC10663390
4

Reig M, Forner A, Rimola J, Ferrer-Fabrega J, Burrel M, Garcia-Criado A, Kelley RK, Galle PR, Mazzaferro V, Salem R, Sangro B, Singal AG, Vogel A, Fuster J, Ayuso C, Bruix J. 2022. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 76(3):681-693. https://doi.org/10.1016/j.jhep.2021.11.018

10.1016/j.jhep.2021.11.01834801630PMC8866082
5

Taddei TH, Brown DB, Yarchoan M, Mendiratta-Lala M, Llovet JM. 2025. Critical Update: AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 82(1):272-274. https://doi.org/10.1097/HEP.0000000000001269

10.1097/HEP.0000000000001269
6

Yao H, Xu W, Shi X, Zhang Z. 2011. Dietary flavonoids as cancer prevention agents. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 29(1):1-31. https://doi.org/10.1080/10590501.2011.551317

10.1080/10590501.2011.551317
7

Aghababaei F, Hadidi M. 2023. Recent advances in potential health benefits of quercetin. Pharmaceuticals (Basel) 16(7):1020. https://doi.org/10.3390/ph16071020

10.3390/ph1607102037513932PMC10384403
8

Pelicano H, Carney D, Huang P. 2004. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat 7(2):97-110. https://doi.org/10.1016/j.drup.2004.01.004

10.1016/j.drup.2004.01.004
9

Nakamura H, Takada K. 2021. Reactive oxygen species in cancer: Current findings and future directions. Cancer Sci 112(10):3945-3952. https://doi.org/10.1111/cas.15068

10.1111/cas.1506834286881PMC8486193
10

Meng X, Franklin DA, Dong J, Zhang Y. 2014. MDM2-p53 pathway in hepatocellular carcinoma. Cancer Res 74(24):7161-7167. https://doi.org/10.1158/0008-5472.CAN-14-1446

10.1158/0008-5472.CAN-14-144625477334PMC4504428
11

Choudhary HB, Mandlik SK, Mandlik DS. 2023. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 14(3):46-70. https://doi.org/10.4291/wjgp.v14.i3.46

10.4291/wjgp.v14.i3.4637304923PMC10251250
12

Lopez-Terrada D, Cheung SW, Finegold MJ, Knowles BB. 2009. Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol 40(10):1512-1515. https://doi.org/10.1016/j.humpath.2009.07.003

10.1016/j.humpath.2009.07.003
13

Arzumanian VA, Kiseleva OI, Poverennaya EV. 2021. The curious case of the HepG2 cell line: 40 years of expertise. Int J Mol Sci 22(23):13135. https://doi.org/10.3390/ijms222313135

10.3390/ijms22231313534884942PMC8658661
14

Fernandez-Palanca P, Fondevila F, Mendez-Blanco C, Tunon MJ, Gonzalez-Gallego J, Mauriz JL. 2019. Antitumor effects of quercetin in hepatocarcinoma in vitro and in vivo models: A systematic review. Nutrients 11(12):2875. https://doi.org/10.3390/nu11122875

10.3390/nu1112287531775362PMC6950472
15

Sethi G, Shanmugam MK, Arfuso F, Kumar AP. 2023. Apoptotic mechanisms of quercetin in liver cancer. Pharmaceutics 15(2):712. https://doi.org/10.3390/pharmaceutics15020712

10.3390/pharmaceutics1502071236840034PMC9960374
16

Granado-Serrano AB, Martin MA, Bravo L, Goya L, Ramos S. 2006. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J Nutr 136(11):2715-2721. https://doi.org/10.1093/jn/136.11.2715

10.1093/jn/136.11.2715
17

Jeon JS, Kwon S, Ban K, Hong YK, Ahn C, Sung JS, Choi I. 2019. Regulation of the intracellular ROS level is critical for the antiproliferative effect of quercetin in the hepatocellular carcinoma cell line HepG2. Nutr Cancer 71(5):861-869. https://doi.org/10.1080/01635581.2018.1559929

10.1080/01635581.2018.155992930661409PMC7513677
18

Hisaka T, Sakai H, Sato T, Goto Y, Nomura Y, Fukutomi S, Fujita F, Mizobe T, Nakashima O, Tanigawa M, Naito Y, Akiba J, Ogasawara S, Nakashima K, Akagi Y, Okuda K, Yano H. 2020. Quercetin suppresses proliferation of liver cancer cell lines in vitro. Anticancer Res 40(8):4695-4700. https://doi.org/10.21873/anticanres.14469

10.21873/anticanres.14469
19

Zhou J, Fang L, Liao J, Li L, Yao W, Xiong Z, Zhou X. 2017. Investigation of the anti-cancer effect of quercetin on HepG2 cells in vivo. PLoS One 12(3):e0172838. https://doi.org/10.1371/journal.pone.0172838

10.1371/journal.pone.017283828264020PMC5338765
20

Maurya AK, Vinayak M. 2015. Anticarcinogenic action of quercetin by downregulation of phosphatidylinositol 3-kinase (PI3K) and protein kinase C (PKC) via induction of p53 in hepatocellular carcinoma (HepG2) cell line. Mol Biol Rep 42(9):1419-1429. https://doi.org/10.1007/s11033-015-3921-7

10.1007/s11033-015-3921-7
21

Guan H, Banh T, Xia K, Tu Y, Le T, Zirngibl RA, Muruve DA, Li X, Smoliakova IP. 2023. Quercetin suppresses hepatocellular carcinoma by inhibiting YY1-mediated p53 demethylation. Metabolites 13(2):229. https://doi.org/10.3390/metabo13020229

10.3390/metabo1302022936837850PMC9968089
22

Zhou J, Fang L, Liao J, Li L, Yao W, Xiong Z, Zhou X. 2016. Investigation of the anti-cancer effect of quercetin on HepG2 cells and its mechanism. Oncol Lett 12(1):516-522. https://doi.org/10.3892/ol.2016.4639

10.3892/ol.2016.463927347174PMC4906932
23

Lee RH, Cho JH, Jeon YJ, Bang W, Cho JJ, Choi NJ, Seo KS, Choi YH, Shim JH, Chae JI. 2015. Quercetin induces antiproliferative activity against human hepatocellular carcinoma (HepG2) cells by suppressing specificity protein 1 (Sp1). Drug Dev Res 76(1):9-16. https://doi.org/10.1002/ddr.21235

10.1002/ddr.21235
24

Zhou J, Liang S, Fang L, Chen L, Tang M, Xu Y, Fu A. 2009. Quantitative proteomics analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS 13(2):93-103. https://doi.org/10.1089/omi.2008.0075

10.1089/omi.2008.0075
25

Che L, Pilo MG, Cigliano A, Latte G, Simile MM, Ribback S, Dombrowski F, Evert M, Chen X, Calvisi DF. 2019. Pathogenetic, prognostic, and therapeutic role of fatty acid synthase in human hepatocellular carcinoma. Front Oncol 9:1412. https://doi.org/10.3389/fonc.2019.01412

10.3389/fonc.2019.0141231921669PMC6927283
26

Li L, Pilo GM, Li X, Cigliano A, Latte G, Che L, Joseph C, Mela M, Wang C, Jiang L, Evert M, Dombrowski F, Ribback S, Calvisi DF, Chen X. 2016. Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans. J Hepatol 64(2):333-341. https://doi.org/10.1016/j.jhep.2015.10.004

10.1016/j.jhep.2015.10.00426476289PMC4718802
27

Zhao P, Mao JM, Zhang SY, Zhou ZQ, Tan Y, Zhang Y. 2014. Quercetin induces HepG2 cell apoptosis by inhibiting fatty acid biosynthesis. Oncol Lett 8(2):765-769. https://doi.org/10.3892/ol.2014.2159

10.3892/ol.2014.215925009654PMC4081423
28

Zhao JL, Zhao J, Jiao HJ. 2014. Synergistic growth-suppressive effects of quercetin and cisplatin on HepG2 human hepatocellular carcinoma cells. Appl Biochem Biotechnol 172(2):784-791. https://doi.org/10.1007/s12010-013-0561-z

10.1007/s12010-013-0561-z
29

Dai W, Gao Q, Qiu J, Yuan J, Wu G, Shen G. 2016. Quercetin induces apoptosis and enhances 5-FU therapeutic efficacy in hepatocellular carcinoma. Tumour Biol 37(5):6307-6313. https://doi.org/10.1007/s13277-015-4501-0

10.1007/s13277-015-4501-0
30

Chen Z, Huang C, Ma T, Jiang L, Tang L, Shi T, Zhang S, Zhang L, Zhu P, Li J, Shen A. 2018. Reversal effect of quercetin on multidrug resistance via FZD7/beta-catenin pathway in hepatocellular carcinoma cells. Phytomedicine 43:37-45. https://doi.org/10.1016/j.phymed.2018.03.040

10.1016/j.phymed.2018.03.040
31

Ji Y, Li L, Ma YX, Li WT, Li L, Zhu HZ, Wu MH, Zhou JR. 2019. Quercetin inhibits growth of hepatocellular carcinoma by apoptosis induction in part via autophagy stimulation in mice. J Nutr Biochem 69:108-119. https://doi.org/10.1016/j.jnutbio.2019.03.018

10.1016/j.jnutbio.2019.03.01831078904PMC9659433
32

Guo Y, Bruno RS. 2015. Endogenous and exogenous mediators of quercetin bioavailability. J Nutr Biochem 26(3):201-210. https://doi.org/10.1016/j.jnutbio.2014.10.008

10.1016/j.jnutbio.2014.10.008
33

Almeida AF, Borge GIA, Piskula M, Tudose A, Tudoreanu L, Valentova K, Williamson G, Santos CN. 2018. Bioavailability of quercetin in humans with a focus on interindividual variation. Compr Rev Food Sci Food Saf 17(3):714-731. https://doi.org/10.1111/1541-4337.12342

10.1111/1541-4337.12342
34

Liu L, Barber E, Kellow NJ, Williamson G. 2025. Improving quercetin bioavailability: A systematic review of human intervention studies. Food Chem 477:143630. https://doi.org/10.1016/j.foodchem.2025.143630

10.1016/j.foodchem.2025.143630
35

Caro C, Pourmadadi M, Eshaghi MM, Rahmani E, Shojaei S, Paiva-Santos AC, Rahdar A, Behzadmehr R, Garcia-Martin ML, Diez-Pascual AM. 2022. Quercetin therapeutic potential: nanomaterials and drug delivery systems. J Drug Deliv Sci Technol 78:103938. https://doi.org/10.1016/j.jddst.2022.103938

10.1016/j.jddst.2022.103938
Information
  • Publisher :Journal of Humanimal Sciences
  • Publisher(Ko) :한경국립대학교 휴머니멀응용과학연구소
  • Journal Title :Journal of Humanimal Sciences
  • Journal Title(Ko) :휴머니멀과학학술지
  • Volume : 2
  • No :2
  • Pages :123-132
  • Received Date : 2026-06-15
  • Accepted Date : 2026-06-16
  • DOI :https://doi.org/10.23341/jhas.2026.2.2.123
Journal Informaiton Journal of Humanimal Sciences Journal of Humanimal Sciences
Online Submission
  • open access
Journal Informaiton Journal Informaiton - close