NFE2L1-mediated proteasome function protects from ferroptosis

Area of Science:

• Cell Biology
• Biochemistry
• Pathology

Background:

• Ferroptosis is a regulated cell death pathway implicated in cancer and degenerative diseases.
• While linked to lipid metabolism, iron homeostasis, and mitochondrial respiration, ferroptosis mechanisms remain incompletely understood.
• Proteasome function is crucial for cellular protein homeostasis, but its role in ferroptosis is unclear.

Purpose of the Study:

• To investigate the role of proteasome function in ferroptosis.
• To identify regulators of proteasome activity during ferroptosis.
• To explore the therapeutic potential of targeting the NFE2L1-proteasome pathway in ferroptosis-related diseases.

Main Methods:

• Utilized cellular systems and patient-derived cell lines (SSMD) with mutated GPX4.
• Investigated the effect of NFE2L1 loss on ferroptosis sensitivity and proteasomal activity.
• Examined ferroptosis hallmarks in Gpx4-deficient and Nfe2l1-deficient mouse models, including brown adipose tissue (BAT) involution.

Main Results:

• Diminished proteasome function is identified as a novel mechanistic feature of ferroptosis.
• Nuclear factor erythroid-2, like-1 (NFE2L1) protects against ferroptosis by sustaining proteasomal activity.
• Loss of NFE2L1 reduced cell viability during ferroptosis induction and was linked to proteasome regulation.
• Reduced proteasomal activity and ferroptosis were observed in GPX4-mutated cells and Gpx4-deficient mice.
• Nfe2l1 deficiency in mice led to BAT involution and ferroptosis hallmarks, including hyperubiquitination of ferroptosis regulators.

Conclusions:

• The NFE2L1-proteasome pathway is critically involved in ferroptosis.
• Targeting NFE2L1 activity may enhance ferroptosis-inducing cancer therapies.
• Modulating NFE2L1 could offer protection against aberrant ferroptosis in neurodegeneration and metabolic disorders.