The involvement of p62–Keap1–Nrf2 antioxidative signaling pathway and JNK in the protection of natural flavonoid quercetin against hepatotoxicity
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.
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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]
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Antioxidants from Plants Protect against Skin Photoaging
Petruk, G., Del Giudice, R., Rigano, M. M., & Monti, D. M. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/1454936 · Cited by 283 · see citing works
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- 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)
- ORCID
- Shi, Liang
- 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
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