CellOct 6, 2026

Glutathione's unexpected role in preventing cell damage by ferroptosis through FSP1

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 7, 2026

Abstract

GSH protects GPX4 knockout cells from ferroptosis via a novel pathway involving FSP1.

GSH's protective role against ferroptosis is not solely reliant on GPX4.
Ferroptosis suppressor protein 1 (FSP1) mediates the GPX4-independent protective effect of GSH.
FSP1 utilizes GSH to produce reduced ubiquinone, which helps eliminate oxidized lipids.
Inhibition of FSP1 disrupts GSH's ability to protect against ferroptosis both in laboratory and living systems.
The GSH-stimulated generation of reduced ubiquinone through FSP1 does not depend on flavin adenine dinucleotide.

Simplified

It is well established that glutathione (GSH) is mainly utilized by glutathione peroxidase 4 (GPX4) to diminish peroxidized phospholipids and defend against ferroptosis. However, we found that GSH robustly protects a variety of GPX4 knockout (KO) cells from ferroptosis, thus indicating that there is an alternative pathway for GSH to suppress ferroptosis. By carrying out genome-wide CRISPR-Cas9 screening, we identified that ferroptosis suppressor protein 1 (FSP1) is the key factor mediating the GPX4-independent protective effect of GSH. Mechanistically, FSP1 uses GSH to generate reduced ubiquinone, which scavenges oxidized lipids and suppresses ferroptosis. Inhibition of FSP1 abolishes this GSH-dependent ferroptosis protection both in vitro and in vivo. Distinct from NAD(P)H-mediated ubiquinone reduction, GSH-stimulated generation of reduced ubiquinone via FSP1 is independent of flavin adenine dinucleotide (FAD). Together, our work clarifies a new mechanism of GSH-mediated ferroptosis suppression, thus highlighting the potential that targeting GSH metabolism should be beneficial for ferroptosis-related diseases whether or not it is related to GPX4.

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Glutathione's unexpected role in preventing cell damage by ferroptosis through FSP1

Abstract

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