New Insights into GPX4 Control of Ferroptosis [Jan. 6, 2026]

1. A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis (Cell, 2025)
Summary: GPX4 is a key enzyme in suppressing ferroptosis, but the importance of its subcellular localization has not been fully elucidated. Using GPX4 variants carrying mutations in the membrane-anchoring fin-loop, this study demonstrates across human iPSC-derived models, organoids, and mice that disruption of this anchoring mechanism is sufficient to trigger ferroptosis, and that GPX4 mislocalization rather than loss of enzymatic activity alone directly underlies ferroptosis-driven neurodegeneration.

Highlighted technique: To evaluate the importance of GPX4 localization, patient-derived primary fibroblasts carrying the R152H mutation in the membrane-anchoring fin-loop of GPX4 were used to analyze the impact of anchor disruption. Lipid peroxidation was assessed using BODIPY 581/591 C11, demonstrating that the R152H mutant exhibits increased accumulation of peroxidized lipids.

2. PRDX6 dictates ferroptosis sensitivity by directing cellular selenium utilization (Molecular Cell, 2024)
Summary: GPX4 is a selenium-dependent phospholipid hydroperoxide reductase and the central suppressor of ferroptosis, whose proper protein expression requires efficient selenium incorporation. Although PRDX6 itself does not directly suppress ferroptosis, this study demonstrates that PRDX6 acts as a selenium-acceptor protein essential for GPX4 synthesis, such that loss of PRDX6 reduces GPX4 abundance and increases ferroptosis sensitivity.

Highlighted technique: Using PRDX6 KO cells, this study shows that loss of PRDX6 markedly reduces GPX4 protein levels without altering GPX4 mRNA expression, demonstrating that PRDX6 is required for GPX4 synthesis rather than transcription. Consistently,PRDX6-deficient mice exhibit a selective reduction of GPX4 expression in the brain, where selenium supply and utilization are physiologically constrained, highlighting the essential role of PRDX6 in maintaining GPX4 abundance under selenium-limited conditions.