Drugging the ferroptotic landscape of Friedreich’s Ataxia: Current paradigms and future directions

Abstract

Friedreich’s ataxia (FRDA) is a rare neurodegenerative condition driven by a severe deficiency of the mitochondrial protein frataxin (FXN). This depletion impairs mitochondrial iron-sulfur cluster biogenesis and disrupts intracellular iron homeostasis, ultimately promoting oxidative stress. Driven by localized iron overload and the continuous generation of reactive oxygen species, the resulting metabolic dysfunction renders vulnerable tissues highly susceptible to ferroptosis. This iron-dependent form of regulated cell death, executed through excessive lipid peroxidation, is now widely acknowledged as an important contributor to the neurodegeneration and hypertrophic cardiomyopathy that characterize FRDA. In the present review, we explore how FXN loss undermines cellular defenses against oxidative damage, placing a specific focus on the regulation of the lipid redox landscape. We detail the breakdown of glutathione (GSH)-dependent mechanisms, specifically highlighting the blunted Nrf2 antioxidant response and the subsequent reduced capacity of glutathione peroxidase 4. Alongside these deficits, we investigate the compensatory roles of GSH-independent rescue networks, namely ferroptosis suppressor protein 1 and mitochondrial dihydroorotate dehydrogenase. Looking toward clinical translation, we critically assess emerging pharmacological interventions designed to target these ferroptotic nodes. The potential of mitochondria-targeted iron chelators, lipoxygenase inhibitors, lipophilic radical-trapping antioxidants, and novel Nrf2 activators is evaluated to determine whether inhibiting ferroptosis can serve as a viable disease-modifying strategy. Moving forward, combinatorial “protect and restore” approaches will likely prove essential for maximizing therapeutic efficacy in FRDA.

Keywords

Friedreich’s ataxia / ferroptosis / Nrf2 / antioxidants / glutathione peroxidase 4 / reactive oxygen species

Acknowledgements

The authors would like to thank Prof. Antonella Russo (Department of Molecular Medicine - DMM, University of Padua) for her precious insights and scientific support.

Authors contribution

Cravin G: Writing-original draft, writing-review & editing. Cozza G: Conceptualization, supervision, writing-original draft, writing-review & editing.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by Associazione “OGNI GIORNO” - per Emma ONLUS and Associazione Per Il Sorriso di Ilaria di Montebruno-ONLUS (Grant No. COZZ_PRIV_CONTRIBUTI25_02).

Copyright

© The Author(s) 2026.

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