Activation of the P62-Keap1-NRF2 Pathway Protects Against Ferroptosis in Hepatocellular Carcinoma Cells

Overview

Journal Hepatology

Specialty Gastroenterology

Date 2015 Sep 26

PMID 26403645

Citations 935

Authors

Xiaofang Sun

Zhanhui Ou

Ruochan Chen

Xiaohua Niu

De Chen

Rui Kang

Daolin Tang

Affiliations

Soon will be listed here.

Abstract

Unlabelled: 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.

Citing Articles

Ferroptosis: a potential target for non-surgical treatment of laryngeal cancer.

Luo Y, He Y, Xu S, Chen Y, Qin F, Hu W Eur Arch Otorhinolaryngol. 2025; .

PMID: 40087171 DOI: 10.1007/s00405-025-09279-y.

Emerging role of ferroptosis in ultraviolet radiation-driven skin photoaging: a narrative review.

Teng Y, Huang Y, Tao X, Fan Y, You J Photochem Photobiol Sci. 2025; .

PMID: 40063311 DOI: 10.1007/s43630-025-00691-1.

From mechanisms to medicine: Ferroptosis as a Therapeutic target in liver disorders.

He Y, Lin Y, Song J, Song M, Nie X, Sun H Cell Commun Signal. 2025; 23(1):125.

PMID: 40055721 PMC: 11889974. DOI: 10.1186/s12964-025-02121-2.

Thirty years of NRF2: advances and therapeutic challenges.

Zhang D Nat Rev Drug Discov. 2025; .

PMID: 40038406 DOI: 10.1038/s41573-025-01145-0.

The molecular and metabolic landscape of ferroptosis in respiratory diseases: Pharmacological aspects.

Wu T, Ji M, Li T, Luo L J Pharm Anal. 2025; 15(1):101050.

PMID: 40034685 PMC: 11873008. DOI: 10.1016/j.jpha.2024.101050.

References

Sasaki H, Sato H, Sato K, Maebara K, Wang H, Tamba M . Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J Biol Chem. 2002; 277(47):44765-71. DOI: 10.1074/jbc.M208704200. View

Dolma S, Lessnick S, Hahn W, Stockwell B . Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003; 3(3):285-96. DOI: 10.1016/s1535-6108(03)00050-3. View

Kowdley K . Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology. 2004; 127(5 Suppl 1):S79-86. DOI: 10.1016/j.gastro.2004.09.019. View

Abou-Alfa G, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A . Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006; 24(26):4293-300. DOI: 10.1200/JCO.2005.01.3441. View

Yagoda N, von Rechenberg M, Zaganjor E, Bauer A, Yang W, Fridman D . RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007; 447(7146):864-8. PMC: 3047570. DOI: 10.1038/nature05859. View

Yang W, Stockwell B . Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008; 15(3):234-45. PMC: 2683762. DOI: 10.1016/j.chembiol.2008.02.010. View

Wang X, Sun Z, Villeneuve N, Zhang S, Zhao F, Li Y . Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008; 29(6):1235-43. PMC: 3312612. DOI: 10.1093/carcin/bgn095. View

Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4):378-90. DOI: 10.1056/NEJMoa0708857. View

Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, Ichimura Y . The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol. 2010; 12(3):213-23. DOI: 10.1038/ncb2021. View

10.

Boettler U, Sommerfeld K, Volz N, Pahlke G, Teller N, Somoza V . Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression. J Nutr Biochem. 2010; 22(5):426-40. DOI: 10.1016/j.jnutbio.2010.03.011. View

11.

Ren D, Villeneuve N, Jiang T, Wu T, Lau A, Toppin H . Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S A. 2011; 108(4):1433-8. PMC: 3029730. DOI: 10.1073/pnas.1014275108. View

12.

Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin. 2011; 61(2):69-90. DOI: 10.3322/caac.20107. View

13.

Tang D, Kang R, Livesey K, Kroemer G, Billiar T, Van Houten B . High-mobility group box 1 is essential for mitochondrial quality control. Cell Metab. 2011; 13(6):701-11. PMC: 3293110. DOI: 10.1016/j.cmet.2011.04.008. View

14.

DeNicola G, Karreth F, Humpton T, Gopinathan A, Wei C, Frese K . Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011; 475(7354):106-9. PMC: 3404470. DOI: 10.1038/nature10189. View

15.

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

16.

Zhou J, Chan L, Zhou S . Trigonelline: a plant alkaloid with therapeutic potential for diabetes and central nervous system disease. Curr Med Chem. 2012; 19(21):3523-31. DOI: 10.2174/092986712801323171. View

17.

Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H . Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012; 22(1):66-79. DOI: 10.1016/j.ccr.2012.05.016. View

18.

Sporn M, Liby K . NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012; 12(8):564-71. PMC: 3836441. DOI: 10.1038/nrc3278. View

19.

Arlt A, Sebens S, Krebs S, Geismann C, Grossmann M, Kruse M . Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene. 2012; 32(40):4825-35. DOI: 10.1038/onc.2012.493. View

20.

Ma Q . Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013; 53:401-26. PMC: 4680839. DOI: 10.1146/annurev-pharmtox-011112-140320. View