2. Academic Validation
  3. Ferroptosis is a novel pathogenic mechanism of FDXR-related disease via disruption of the NRF2 pathway

Ferroptosis is a novel pathogenic mechanism of FDXR-related disease via disruption of the NRF2 pathway

  • Cell Death Discov. 2025 Dec 23;11(1):563. doi: 10.1038/s41420-025-02840-y.
Teresa Campbell # 1 2 3,  Jesse Slone # 1 2 3,  Jimmy Vu 1,  Wensheng Liu 1,  Li Yang 2 4,  Adam Dourson 5,  Luis F Queme 5 6,  Michael P Jankowski 3 5,  Taosheng Huang 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
  • 2 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 3 College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
  • 4 Department of Pediatrics, Xiangya Hospital; Central South University, Changsha, China.
  • 5 Department of Anesthesia, Division of Pain Management, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 6 Department of Biomedical Sciences, University of New England College of Osteopathic Medicine, Biddeford, ME, USA.
  • 7 Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA. [email protected].
  • 8 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. [email protected].
  • 9 College of Medicine, University of Cincinnati, Cincinnati, OH, USA. [email protected].
  • 10 Institute of Medical Genetics & Genomics, Fudan University, 1st Floor, Building B, Suite 1027, Research Building 2, No. 131 Dong'an Road, Xuhui District, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41436440 DOI: 10.1038/s41420-025-02840-y
Abstract

Loss-of-function variants in the ferredoxin reductase (FDXR) gene result in a primary mitochondrial disease in humans, involving abnormal mitochondrial iron accumulation. However, the molecular mechanism is not fully understood. To better understand the underlying pathology of FDXR-related disease, we generated a mouse model corresponding to the hotspot variant found in humans. We demonstrated increased lipid peroxidation in the inner mitochondrial and plasma membranes, resulting in susceptibility to Ferroptosis. Closer examination revealed that disruption of the NRF2 pathway and its target gene SLC7A11 appear to play important roles in this pathogenic process. Finally, administration of the NRF2 activator omaveloxolone, which was recently approved by the FDA for treatment of Friedreich's ataxia, helps mitigate the pathogenesis. Together, our results suggest that Ferroptosis is a novel underlying mechanism of FDXR-related disease and that activation of NRF2 could be an immediate, viable treatment option for individuals with FDXR-related disease and Other conditions involving aberrant iron metabolism.

Figures
Products