Clockophagy is a novel selective autophagy process favoring ferroptosis

Minghua Yang, Pan Chen, Jiao Liu, Shan Zhu, Guido Kroemer, Daniel J. Klionsky, Michael T. Lotze, Herbert J. Zeh, Rui Kang, Daolin Tang

Research output: Contribution to journalArticlepeer-review

249 Scopus citations


Ferroptosis is a form of nonapoptotic regulated cell death driven by iron-dependent lipid peroxidation. Autophagy involves a lysosomal degradation pathway that can either promote or impede cell death. A high level of autophagy has been associated with ferroptosis, but the mechanisms underpinning this relationship are largely elusive. We characterize the contribution of autophagy to ferroptosis in human cancer cell lines and mouse tumor models. We show that “clockophagy,” the selective degradation of the core circadian clock protein ARNTL by autophagy, is critical for ferroptosis. We identify SQSTM1 as a cargo receptor responsible for autophagic ARNTL degradation. ARNTL inhibits ferroptosis by repressing the transcription of Egln2, thus activating the prosurvival transcription factor HIF1A. Genetic or pharmacological interventions blocking ARNTL degradation or inhibiting EGLN2 activation diminished, whereas destabilizing HIF1A facilitated, ferroptotic tumor cell death. Thus, our findings reveal a new pathway, initiated by the autophagic removal of ARNTL, that facilitates ferroptosis induction.

Original languageEnglish (US)
Article numbereaaw2238
JournalScience Advances
Issue number7
StatePublished - Jul 24 2019

ASJC Scopus subject areas

  • General


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