Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease Original paper

What was reviewed?

This Primer reviewed ferroptosis as a regulated form of cell death that occurs when iron-dependent lipid hydroperoxides accumulate to lethal levels. It explained ferroptosis as an “Achilles’ heel” created by polyunsaturated fatty acids in membranes, and it framed cell survival as a balance between lipid peroxide generation and multiple repair or detox systems. The paper emphasized how ferroptosis sits at the crossroads of amino acid metabolism, glutathione biology, lipid remodeling, iron trafficking, and redox control, and it summarized where ferroptosis likely contributes to disease and where clinicians may be able to modulate it.

Who was reviewed?

Because this is a review, the authors did not analyze one patient cohort. Instead, they synthesized evidence drawn from diverse experimental settings, including mammalian cell systems, organ and tissue injury models, neurodegeneration models, and cancer models. They also referenced plant stress models to underscore that ferroptosis-like vulnerability is evolutionarily conserved. The review repeatedly connected mechanism to clinically recognizable contexts such as ischemia–reperfusion injury, hemorrhagic and traumatic brain injury, kidney degeneration, and carcinogenesis, focusing on what is consistent across systems rather than any single disease population.

What were the most important findings?

The review clarified that ferroptosis is defined by lethal lipid peroxidation that depends on iron availability and on the presence of peroxidation-prone polyunsaturated phospholipids. It highlighted GPX4 and glutathione as core defenses that detoxify lipid hydroperoxides, and it explained how limiting cystine import through system xc− can deplete glutathione and permit unchecked lipid damage. It also emphasized that membrane lipid remodeling enzymes, including ACSL4 and LPCAT3, shape susceptibility by determining whether arachidonic and adrenic acid–containing phospholipids become abundant substrates for oxidation, while iron uptake, ferritin handling, and ferritinophagy tune the labile iron pool that fuels this process.

What are the greatest implications of this study/ review?

This review gives clinicians a practical map for thinking about ferroptosis as a modifiable injury pathway rather than a niche laboratory phenomenon. It supports two translational directions: inducing ferroptosis to exploit metabolic and redox fragility in selected cancers, and inhibiting ferroptosis to limit tissue loss in conditions marked by oxidative stress and iron dysregulation. It also warns that ferroptosis readouts are sensitive to nutrient and antioxidant context, which matters for interpreting biomarkers and for designing interventions that change iron status, lipid availability, or antioxidant capacity.