Cited by 169Genomics, phytochemicals, and oxidative stressDrug-Induced Hepatotoxicity and ProtectionFlavonoids in Medical Research

The involvement of p62–Keap1–Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity

Ji, Li-Li, Sheng, Yu-Chen, Zheng, Zhi-Yong, Shi, Liang, Wang, Zheng-Tao·2015·Free Radical Biology and Medicine

Abstract

Quercetin, one of the most abundant dietary flavonoids, is reported to have protective function against various hepatotoxicant-induced hepatotoxicity. The present study aims to investigate the critical role of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidative signaling pathway in the protection of quercetin against hepatotoxicity. Quercetin prevented the cytotoxicity induced by a variety of hepatotoxicants including clivorine (Cliv), acetaminophen (APAP), ethanol, carbon tetrachloride (CCl4), and toosendanin (TSN) in human normal liver L-02 cells. Quercetin induced the nuclear translocation of Nrf2, along with the increased expression of the antioxidant responsive element (ARE)-dependent genes like catalytic or modify subunit of glutamate-cysteine ligase (GCLC/GCLM), and heme oxygenase-1 (HO-1). In addition, the HO-1 inhibitor zinc protoporphyrin (ZnPP) and the GCL inhibitor L-buthionine-(S,R)-sulfoximine (BSO) both reduced the hepatoprotection induced by quercetin. Quercetin had no effect on kelch-like ECH-associated protein-1(Keap1) expression, but molecular docking results indicated the potential interaction of quercetin with the Nrf2-binding site in Keap1 protein. Quercetin increased the expression of p62, and p62 siRNA decreased quercetin-induced hepatoprotection. Quercetin induced the activation of c-Jun N-terminal kinase (JNK) in hepatocytes. JNK inhibitor SP600125 and JNK siRNA both reduced quercetin-induced hepatoprotection. SP600125 and JNK siRNA decreased the increased p62 expression induced by quercetin. In addition, SP600125 also decreased the increased mRNA and protein expression of GCLC, GCLM, and HO-1 induced by quercetin. Taken together, our present study demonstrates that quercetin prevents hepatotoxicity by inducing p62 expression, inhibiting the binding of Keap1 to Nrf2, and thus leading to the increased expression of antioxidative genes dependent on Nrf2. Meanwhile, our study indicates that JNK plays some regulation in this process.

Integrity signals

Registry

Crossref · 10.1016/j.freeradbiomed.2015.03.035

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Antioxidants can regulate gene expression by inducing translocation of Nrf-2 from the cytosol to the nucleus, binding ARE, and inducing transcription of stress response genes GST, HO-1, and NQO1.

    “In addition, antioxidants can regulate gene expression inducing the translocation of the nuclear factor-erythroid 2-related factor 2 (Nrf-2) from the cytosol to the nucleus, upon dissociation from its inhibitor, Kelch-like erythroid cell-derived protein 1 (Keap-1).”

    From Antioxidants from Plants Protect against Skin Photoaging (2018) · cites this paper as [63]

Cites

1 retracted

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Ji, L.-L., Sheng, Y.-C., Zheng, Z.-Y., Shi, L., & Wang, Z.-T.
Affiliations
State Administration of Traditional Chinese Medicine of the People's Republic of China (CN)
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2015-08
Volume
85
Pages
12-23
ISSN
0891-5849 (ISSN-L)
OpenAlex
W2046266642
Cited by
169
References
37
Citations by year
2026: 7 · 2025: 10 · 2024: 18 · 2023: 15 · 2022: 11 · 2021: 16 · 2020: 16 · 2019: 14 · 2018: 22 · 2017: 18 · 2016: 19 · 2015: 3
FWCI
8.97
Type
journal article
Language
en
Open access
closed
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81322053)
  • Shanghai Municipal Education Commission and Shanghai Education Development Foundation (13SG43)
  • New Century Excellent Talents in University (NCET-11-1054)
  • State major science and technology (2015ZX09501004-002-002)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
Keywords
quercetin, hepatotoxicity, Nrf2 signaling, p62, Keap1, JNK, hepatoprotection, glutathione synthesis, heme oxygenase-1, paracetamol, carbon tetrachloride, ethanol, toosendanin, flavonoids, zinc protoporphyrin, SP600125
MeSH terms
Kelch-Like ECH-Associated Protein 1, Cell Line, Humans, Liver, Oxidation-Reduction, Quercetin, Signal Transduction, Transcriptional Activation, RNA-Binding Proteins, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase 4, NF-E2-Related Factor 2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review