# Ferroptosis and Cuproptosis in Cancer and Neurodegeneration: A Comprehensive Review of Modulation by Iron and Copper Chelators and Related Agents

## TL;DR

This review explores how imbalances in iron and copper cause cell death in cancer and neurodegenerative diseases, and how chelators and other agents can be used to control these processes for treatment.

## Contribution

The paper provides a comprehensive analysis of how iron and copper chelators modulate ferroptosis and cuproptosis for cancer therapy and neuroprotection.

## Key findings

- Bimetallic nanoplatforms and CRISPR-Cas9 nano-ionophores exploit iron addiction to induce cancer cell death.
- Neuroprotection strategies use brain-penetrant chelators like SK4 and antioxidants like CuII(atsm).
- Copper deficiency inactivates ferroxidases, leading to iron-dependent ferroptosis and oxidative damage.

## Abstract

Dysregulation of iron and copper homeostasis is a pivotal driver of regulated cell death through two distinct yet interconnected modalities: ferroptosis and cuproptosis. This comprehensive review evaluates the therapeutic modulation of these metal-driven pathways within a dual paradigm: their deployment as a cytotoxic weapon in oncology and their inhibition for neuroprotection. We synthesize evidence ranging from small-molecule synergy to advanced nanomedicine, examining how the interplay between iron and copper governs cellular fate in resistant malignancies and neurodegenerative diseases such as Parkinson’s disease and Multiple Sclerosis. In oncology, bimetallic nanoplatforms and CRISPR-Cas9 nano-ionophores exploit “iron addiction” and metabolic vulnerabilities to induce fatal lipid peroxidation and FDX1-mediated proteotoxic stress, often by circumventing efflux transporters like ATP7A/B. Conversely, neuroprotective strategies focus on site-specific chelation, utilizing brain-penetrant molecules like SK4 (targeting the LAT1 transporter) and radical trapping antioxidants like CuII(atsm). Importantly, we elucidate the “iron trap” mechanism, where copper deficiency inactivates multicopper ferroxidases—including ceruloplasmin and hephaestin—thereby triggering iron-dependent ferroptosis. Our analysis reveals a self-amplifying cycle of oxidative damage driven by metal-induced ATP depletion and glutathione exhaustion. By delineating the molecular machinery of iron and copper metabolism, this article provides a roadmap for leveraging regulated cell death to overcome apoptosis resistance in cancer and preserve neural integrity in chronic degeneration.