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Activation of the p62–Keap1–NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells
Open accessAbstract
Ferroptosis is a recently recognized form of regulated cell death caused by an iron‐dependent accumulation of lipid reactive oxygen species. However, the molecular mechanisms regulating ferroptosis remain obscure. Here, we report that nuclear factor erythroid 2‐related factor 2 (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Upon exposure to ferroptosis‐inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch‐like ECH‐associated protein 1. Additionally, nuclear NRF2 interacted with transcriptional coactivator small v‐maf avian musculoaponeurotic fibrosarcoma oncogene homolog proteins such as MafG and then activated transcription of quinone oxidoreductase‐1, heme oxygenase‐1, and ferritin heavy chain‐1. Knockdown of p62, quinone oxidoreductase‐1, heme oxygenase‐1, and ferritin heavy chain‐1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib. Furthermore, genetic or pharmacologic inhibition of NRF2 expression/activity in HCC cells increased the anticancer activity of erastin and sorafenib in vitro and in tumor xenograft models. Conclusion: These findings demonstrate novel molecular mechanisms and signaling pathways of ferroptosis; the status of NRF2 is a key factor that determines the therapeutic response to ferroptosis‐targeted therapies in HCC cells. (H epatology 2016;63:173–184)
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“Phosphorylation of p62 initiates its interaction with E3 ligase KEAP1, therefore competing out alternate KEAP1 target Nrf2 and stabilizing Nrf2 signaling [102].”
From Acetylation: a new target for protein degradation in cancer (2025) · cites this paper as [102]
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Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Sorafenib in advanced hepatocellular carcinoma
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Regulation of Ferroptotic Cancer Cell Death by GPX4
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A New Era of Systemic Therapy for Hepatocellular Carcinoma with Regorafenib and Lenvatinib
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Sorafenib in Advanced Hepatocellular Carcinoma
정, 재. (2008) · Cited by 5,586
Role of nrf2 in oxidative stress and toxicity
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Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
Friedmann Angeli, J. P., Schneider, M., Proneth, B., Tyurina, Y. Y., Tyurin, V. A., Hammond, V. J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3064 · Cited by 3,732
Ferroptosis as a p53-mediated activity during tumour suppression
Jiang, L., Kon, N., Li, T., Wang, S.-J., Su, T., Hibshoosh, H., Baer, R., & Gu, W. (2015) · Nature · doi:10.1038/nature14344 · Cited by 3,398
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Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.021 · Cited by 7,695
Self-citationFerroptosis: mechanisms, biology and role in disease
Jiang, X., Stockwell, B. R., & Conrad, M. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00324-8 · Cited by 7,973
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680
Ferroptosis: molecular mechanisms and health implications
Tang, D., Chen, X., Kang, R., & Kroemer, G. (2020) · Cell Research · doi:10.1038/s41422-020-00441-1 · Cited by 4,495
Self-citationFerroptosis: past, present and future
Li, J., Cao, F., Yin, H.-L., Huang, Z.-J., Lin, Z.-T., Mao, N., Sun, B., & Wang, G. (2020) · Cell Death & Disease · doi:10.1038/s41419-020-2298-2 · Cited by 4,171
Metadata
- Authors
- Sun, X., Ou, Z., Chen, R., Niu, X., Chen, D., Kang, R., & Tang, D.
- Affiliations
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- University of Pittsburgh (US)
- Corresponding author
- Tang, Daolin
- Venue
- Hepatology
- Published
- 2015-11-26
- Volume
- 63
- Issue
- 1
- Pages
- 173-184
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC4688087
- OpenAlex
- W2163005196
- Cited by
- 2,012
- References
- 40
- Citations by year
- 2026: 165 · 2025: 255 · 2024: 311 · 2023: 309 · 2022: 342 · 2021: 255 · 2020: 165 · 2019: 92 · 2018: 52 · 2017: 30 · 2016: 26 · 2015: 2
- FWCI
- 29.04
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-08-01)
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pittsburgh
- National Natural Science Foundation of China (201508020258, R01GM115366, 201400000003, R01CA160417, 81502445, 31171229, U1132005)
- National Institutes of Health (R01GM115366 to D.T.)
- National Cancer Institute (R01CA160417)
- National Institute of General Medical Sciences (R01GM115366)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- ferroptosis, Nrf2, p62, Keap1, hepatocellular carcinoma, erastin, sorafenib, buthionine sulfoximine, quinone oxidoreductase 1, heme oxygenase-1, FTH1, MAFG, ferroptosis-targeted therapy, iron-dependent lipid peroxidation
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Animals, Carcinoma, Hepatocellular, Humans, Iron, Liver Neoplasms, Mice, Inbred C57BL, Tumor Cells, Cultured, Signal Transduction, RNA-Binding Proteins, Cell Death, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2, Mice
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