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

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

Research output: Contribution to journalArticle

260 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)173-184
Number of pages12
JournalHepatology
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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