A non-canonical function of glutathione to suppress ferroptosis via FSP1.

GSH suppresses ferroptosis independently of GPX4 by activating FSP1 to generate reduced ubiquinone, with 90% reliance on this pathway in knockout cells.

• Why it matters: Ferroptosis plays a critical role in various diseases, but the mechanisms beyond GPX4 are poorly understood, limiting therapeutic options for ferroptosis-related conditions.
• What they did: Using genome-wide CRISPR-Cas9 screening, the study identified FSP1 as a key mediator of GSH’s GPX4-independent ferroptosis suppression, revealing a new GSH-dependent pathway involving ubiquinone reduction.
• The result: This discovery uncovers a novel GSH-FSP1 pathway that can be targeted to control ferroptosis, offering potential strategies for treating diseases linked to ferroptosis regardless of GPX4 activity.