Cited by 2,012Ferroptosis and cancer prognosisGenomics, phytochemicals, and oxidative stressIron Metabolism and Disorders

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Activation of the p62–Keap1–NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells

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Sun, Xiaofang, Ou, Zhanhui, Chen, Ruochan, Niu, Xiaohua, Chen, De, Kang, Rui, Tang, Daolin·2016·Hepatology

DOI 10.1002/hep.28251PMC PMC4688087

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Abstract

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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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
ORCID: Sun, Xiaofang
Ou, Zhanhui
Chen, Ruochan
Niu, Xiaohua
Chen, De
Kang, Rui
Tang, Daolin
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2015-11-26
Volume: 63
Issue: 1
Pages: 173-184
ISSN: 0270-9139 (ISSN-L)
1527-3350
DOI: 10.1002/hep.28251
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
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm)
onlinelibrary.wiley.com/termsAndConditions (vor)
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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Activation of the p62–Keap1–NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells

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