Ferrostatin-1
[CAS# 347174-05-4]

Identification

• Classification: Biochemical >> Inhibitor >> Metabolism >> Ferroptosis inhibitor
• Name: Ferrostatin-1
• Synonyms: ethyl 3-amino-4-(cyclohexylamino)benzoate
• Molecular Formula: C₁₅H₂₂N₂O₂
• Molecular Weight: 262.35
• CAS Registry Number: 347174-05-4
• EC Number: 803-483-3
• SMILES: CCOC(=O)C1=CC(=C(C=C1)NC2CCCCC2)N

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Boiling point: 437.3±35.0 °C 760 mmHg (Calc.)^*
• Flash point: 218.3±25.9 °C (Calc.)^*
• Solubility: 100 mM (DMSO), 100 mM (ethanol) (Expl.)
• Index of refraction: 1.595 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P271-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335

Discovery and Applications

Ferrostatin-1 is a small-molecule compound first reported in 2012 in the context of its ability to selectively inhibit ferroptosis, a regulated form of non-apoptotic cell death associated with iron-dependent lipid peroxidation. Its discovery emerged from high-throughput chemical screening aimed at identifying agents that could suppress oxidative, iron-dependent cell death processes distinct from apoptosis or necrosis. The identification of Ferrostatin-1 contributed significantly to establishing ferroptosis as a distinct form of cell death and laid the groundwork for deeper investigation into lipid metabolism, redox biology, and cellular iron homeostasis.

Chemically, Ferrostatin-1 is classified as an aromatic amine bearing a lipophilic moiety that allows it to interact with lipid membranes. Its structure contributes to its function by enabling it to act as a potent scavenger of lipid peroxyl radicals. This mechanism plays a key role in its capacity to inhibit the chain reaction of lipid peroxidation, which underlies the cytotoxic process of ferroptosis. Unlike conventional antioxidants, Ferrostatin-1 does not rely on general redox reactions but rather exhibits selective inhibition by targeting specific cellular contexts where lipid hydroperoxides accumulate in an iron-dependent manner.

Ferrostatin-1’s utility was initially demonstrated in mammalian cell lines exposed to inhibitors of the cystine/glutamate antiporter system x_c⁻, such as erastin. In such conditions, glutathione depletion impairs the function of glutathione peroxidase 4 (GPX4), a selenoenzyme critical for reducing lipid hydroperoxides. This failure leads to unchecked lipid peroxidation and cell death, which Ferrostatin-1 is able to prevent by intervening downstream of glutathione depletion and GPX4 inhibition.

Subsequent studies broadened the range of biological models where Ferrostatin-1 showed efficacy. It has demonstrated protective effects in cellular and animal models of neurodegeneration, ischemia-reperfusion injury, acute kidney injury, and various inflammatory pathologies. In many of these contexts, oxidative stress and lipid peroxidation are central contributors to cell damage, particularly in tissues with high metabolic rates or dense mitochondrial networks. The compound's ability to preserve membrane integrity and prevent iron-dependent lipid damage has made it a valuable pharmacological probe for studying oxidative cell death pathways.

Despite its widespread use in preclinical models, Ferrostatin-1 has not advanced to clinical application due to issues including metabolic instability and lack of optimal pharmacokinetic properties. Nonetheless, it remains a reference compound in experimental systems for dissecting ferroptosis-related mechanisms. It has also inspired the development of second-generation ferroptosis inhibitors, such as liproxstatin-1 and other analogs with improved drug-like properties.

Ferrostatin-1 has also provided insights into disease mechanisms. In cancer research, for instance, it has been used to probe tumor cell vulnerabilities associated with ferroptosis sensitivity, especially in cancers harboring mutations that disrupt redox homeostasis. Conversely, in the context of degenerative diseases, Ferrostatin-1 has been applied to understand how ferroptotic processes contribute to neuronal and organ damage. Its use has elucidated the role of lipid peroxidation in multiple models of pathology, providing a conceptual framework for potential therapeutic interventions targeting ferroptosis.

Ferrostatin-1 continues to be employed in basic research to differentiate ferroptosis from other cell death processes, such as apoptosis, autophagy, and necroptosis. It serves as a benchmark for evaluating the potency of new ferroptosis inhibitors and remains a central tool in molecular and cellular biology laboratories focused on oxidative cell death.

References

2012. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death. Cell, 149(5).
DOI: 10.1016/j.cell.2012.03.042

2014. Ferrostatins Inhibit Oxidative Lipid Damage and Cell Death in Diverse Disease Models. Journal of the American Chemical Society, 136(10).
DOI: 10.1021/ja411006a

2024. Ferrostatin-1 ameliorates Cis-dichlorodiammineplatinum(II)-induced ovarian toxicity by inhibiting ferroptosis. Molecular Medicine, 30(1).
DOI: 10.1186/s10020-024-00923-7