Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors Original paper

What was reviewed?

This review summarized the current landscape of ferroptosis inhibitors and argued that blocking phospholipid peroxidation remains the most effective way to stop ferroptosis across disease contexts. The authors framed ferroptosis as an iron-catalyzed, regulated form of necrotic cell death that depends on membrane phospholipid peroxidation, and they positioned ferrostatin-1 as the historical benchmark while emphasizing that newer inhibitors improve potency and in vivo usefulness. They reviewed both endogenous defense systems and synthetic drug-like compounds, with a deliberate focus on radical-trapping antioxidants because these agents directly terminate lipid radical chain reactions at the membrane level and have generated the strongest proof-of-concept protection in animal disease models.

Who was reviewed?

Because this was a review, it did not evaluate one patient group. Instead, it integrated evidence from diverse experimental systems used across the ferroptosis field, including cell-based ferroptosis assays triggered by canonical inducers and multiple in vivo disease models where ferroptosis inhibition changes outcomes. The paper also drew from pharmacology and medicinal chemistry work that compares potency, stability, solubility, and exposure constraints that determine whether a ferroptosis inhibitor can realistically function in animals and, eventually, humans.

What were the most important findings?

The review’s central conclusion was that lipophilic radical-trapping antioxidants outperform many “upstream” targeted approaches because ferroptosis ultimately executes through lipid autoxidation in membranes, and radical-trapping chemistry can stop that chain reaction directly. It highlighted that the biological defense network includes multiple endogenous radical-trapping systems beyond GPX4, including vitamin E, coenzyme Q, tetrahydrobiopterin, vitamin K, and hydropersulfides, which together reinforce that ferroptosis control is fundamentally about maintaining membrane redox stability. The authors also clarified a practical point for interpreting the inhibitor literature: several agents labeled as lipoxygenase inhibitors can appear protective largely because they also behave as radical-trapping antioxidants, and assay conditions can substantially change apparent potency, making reference standards essential. Finally, the review emphasized that medicinal chemistry progress has produced newer radical-trapping inhibitors with improved stability and tolerability that enable successful in vivo studies, supporting ferroptosis inhibition as a realistic therapeutic strategy rather than only a cell-culture phenomenon.

What are the greatest implications of this study/ review?

For clinicians and translational teams, this review supports ferroptosis inhibition as a credible therapeutic concept in conditions where iron-driven oxidative membrane injury contributes to pathology, while also setting expectations for what will likely work best in practice. It suggests that interventions that directly suppress lipid peroxidation may translate more reliably than approaches that target a single upstream protein, because multiple metabolic routes can converge on the same final lipid radical pathway. It also highlights a key development barrier: the most effective inhibitors must combine membrane-localized radical trapping with acceptable pharmacokinetics and organ distribution, especially for indications requiring brain penetration or chronic dosing. Overall, the review positions optimized radical-trapping antioxidants as the current front-runners for near-term in vivo and translational progress, while encouraging biomarker development to track ferroptosis activity in patients.