image: The ferroptotic landscape in Friedreich's ataxia. Frataxin deficiency in the mitochondrion leads to ISC failure and ROS generation. Simultaneously, impaired cellular defenses, characterized by Nrf2 downregulation, lead to decreased GSH levels and defective GPx4 activity. In the cytosol, aberrant IRP1 activation increases the labile iron pool through enhanced transferrin-mediated iron import and NCOA4-mediated ferritinophagy. At the membrane level, lipid remodeling (orange arrows) is driven by PLA2 which generates LPLs, while ACSL4 activates free PUFAs into PUFA-CoAs, which are subsequently esterified into the membrane by LPCAT3 to form highly vulnerable PUFA-PEs. The convergence of accumulated iron, ROS, and ACSL4-mediated incorporation of PUFA-PEs into the membrane results in unchecked LPO, ultimately driving ferroptotic cell death. Green upward arrows denote upregulation or accumulation; red downward arrows denote downregulation or functional impairment. Created in BioRender. Cozza, G. (2026) https://BioRender.com/9m8dus3. ISC: iron-sulfur cluster; ROS: reactive oxygen species; Nrf2: nuclear factor erythroid 2-related factor 2; GSH: glutathione; GPx4: glutathione peroxidase 4; IRP1: iron regulatory protein 1; NCOA4: nuclear receptor coactivator 4; PLA2: phospholipase A2; LPLs: lysophospholipids; ACSL4: Acyl-CoA synthetase long-chain family member 4; LPCAT3: lysophosphatidylcholine acyltransferase 3; PUFA-PE: polyunsaturated fatty acid-phosphatidylethanolamines; LPO: lipid peroxidation.
Credit: © Cravin G, Cozza G, 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
A new review article highlights ferroptosis as a promising therapeutic target in Friedreich's Ataxia and outlines emerging strategies to translate ferroptosis biology into treatment opportunities.
Published in the open-access journal Ferroptosis and Oxidative Stress, the review by Giovanni Cravin and Giorgio Cozza from the University of Padua examines the growing evidence linking ferroptosis to the pathogenesis of Friedreich's Ataxia (FRDA), a rare inherited neurodegenerative disease characterized by progressive neurological decline, cardiomyopathy, and premature mortality.
Friedreich's Ataxia is caused by deficiency of frataxin, a mitochondrial protein essential for iron–sulfur cluster biogenesis and cellular energy metabolism. Loss of frataxin disrupts mitochondrial function, promotes oxidative stress, and leads to abnormal iron accumulation—hallmarks that closely resemble the molecular conditions known to trigger ferroptosis.
Ferroptosis is an iron-dependent form of regulated cell death driven by excessive lipid peroxidation. Although initially studied primarily in cancer biology, ferroptosis has increasingly been implicated in neurodegenerative disorders, where dysregulated iron metabolism and oxidative damage contribute to neuronal loss. According to the authors, FRDA may represent one of the most compelling examples of a disease in which multiple ferroptosis-promoting mechanisms converge.
The review summarizes how frataxin deficiency creates a cellular environment highly susceptible to ferroptotic damage. Mitochondrial iron overload, impaired antioxidant defenses, reactive oxygen species accumulation, and lipid peroxidation collectively establish conditions that may accelerate degeneration of both nervous and cardiac tissues.
Importantly, the article moves beyond disease mechanisms to examine therapeutic opportunities. The authors discuss a broad range of pharmacological strategies that could modulate ferroptotic pathways in FRDA, including iron chelators, antioxidants, lipid peroxidation inhibitors, mitochondrial-targeted therapies, and emerging ferroptosis-specific interventions. Several of these approaches have already demonstrated encouraging results in preclinical studies, suggesting that ferroptosis-targeted therapies may offer new avenues for disease modification.
The review also highlights a major shift in the field. Rather than viewing iron accumulation and oxidative stress as isolated pathological features, researchers are increasingly recognizing them as interconnected components of a ferroptotic network. Understanding this network could help explain disease progression and reveal new therapeutic vulnerabilities.
As interest in ferroptosis continues to expand beyond oncology, Friedreich's Ataxia may provide an important model for understanding how ferroptotic mechanisms contribute to human neurodegenerative disease. The authors argue that integrating advances in ferroptosis biology with FRDA research could accelerate the development of more effective therapies for a disease that currently lacks curative treatment options.
Method of Research
Literature review
Subject of Research
Not applicable
Article Title
Drugging the ferroptotic landscape of Friedreich’s Ataxia: Current paradigms and future directions
Article Publication Date
16-Jun-2026
COI Statement
The authors declare no conflicts of interest.