Clockophagy is a novel selective autophagy process favoring ferroptosis

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• Ferroptosis is regulated cell death driven by iron-dependent lipid peroxidation.
• Autophagy, a lysosomal degradation pathway, can influence cell death, but its role in ferroptosis is unclear.
• A link between high autophagy levels and ferroptosis has been observed, yet the underlying mechanisms remain largely unknown.

Purpose of the Study:

• To investigate the contribution of autophagy to ferroptosis in human cancer cells and mouse tumor models.
• To elucidate the molecular mechanisms connecting autophagy and ferroptosis.

Main Methods:

• Characterization of autophagy's role in ferroptosis using human cancer cell lines and mouse tumor models.
• Identification of specific proteins and pathways involved in the autophagic regulation of ferroptosis.
• Genetic and pharmacological manipulations to assess the impact on ferroptosis induction.

Main Results:

• 'Clockophagy,' the selective autophagic degradation of the circadian clock protein ARNTL, was identified as critical for ferroptosis.
• SQSTM1 was identified as the cargo receptor mediating autophagic ARNTL degradation.
• ARNTL was found to inhibit ferroptosis by repressing *Egln2* transcription, thereby activating the prosurvival factor HIF1A.
• Blocking ARNTL degradation or EGLN2 activation reduced ferroptosis, while HIF1A destabilization enhanced it.

Conclusions:

• Autophagic removal of ARNTL (clockophagy) is a novel pathway that facilitates ferroptosis induction.
• This pathway involves ARNTL-mediated repression of *Egln2* and subsequent HIF1A activation.
• Targeting clockophagy or downstream components offers potential therapeutic strategies for enhancing ferroptosis in cancer treatment.