# Ferroptosis: Mechanisms, Comparison with Cuproptosis and Emerging Horizons in Therapeutics

## TL;DR

This paper reviews ferroptosis, a type of cell death caused by iron and lipid peroxidation, and compares it with cuproptosis, highlighting its role in cancer and potential therapies.

## Contribution

The paper provides a comprehensive overview of ferroptosis mechanisms, its distinction from cuproptosis, and its therapeutic implications in cancer.

## Key findings

- Ferroptosis involves lipid peroxidation and specific metabolic pathways like the System Xc−-glutathione peroxidase 4 axis.
- Cuproptosis differs from ferroptosis by relying on copper ions and ferredoxin 1-mediated protein aggregation.
- Sensitivity to ferroptosis varies in cancers due to metabolic signatures and antioxidant regulators like Acyl-CoA synthetase long-chain family member 4.

## Abstract

Ferroptosis is an iron-dependent, excessive lipid peroxidation-driven form of regulated cell death. The core mechanisms of ferroptosis include lipid peroxidation cascade, System Xc−-glutathioneglutathione peroxidase 4 axis, iron and lipid metabolism chaos, the NAD(P)Hferroptosis suppressor protein 1—ubiquinone axis, and GTP cyclohydrolase 1 tetrahydrobiopterin-dihydrofolate reductase axis. Cuproptosis is triggered by copper ions and involves ferredoxin 1-mediated aggregation of lipoylated proteins, differing fundamentally from ferroptosis. Both ferroptosis and cuproptosis exhibit dual roles (promote or inhibit) in cancers. And the sensitivity of different cancer types to ferroptosis varies, which may depend on special metabolic signatures (e.g., E-cadherin loss causes epithelial–mesenchymal transition, making tumors gain resistance to ferroptosis) and expression of antioxidant defense regulators (e.g., high expression of Acyl-CoA synthetase long-chain family member 4 and lncFASA make tumors easily sensitive). At present, traditional Chinese herbal medicine, combination therapy, and nano-delivery technology correlated with ferroptosis are being hotly studied by researchers in order to realize clinical translation of ferroptosis. In this review, we have summarized the core mechanisms of ferroptosis, ferroptosis differences from cuproptosis, its impact on cancers, and its translational implications in cancer therapy, helping readers quickly get the new information and horizons on them.