NRF2 Coordinates Ferroptosis and Disulfidptosis in Dermal Papilla Cells via Redox Metabolic Reprogramming in Androgenetic Alopecia.

Summary

Using primary cells, organoids, and DHT-mouse models, the authors show NRF2 downregulation in AGA and mechanistically link it to ferroptosis (via SLC7A11–GSH–GPX4 suppression) and disulfidptosis (via PPP impairment and NADPH depletion). Pharmacologic NRF2 activation with dimethyl fumarate mitigated both death programs and restored hair growth, nominating NRF2 as a therapeutic target.

Key Findings

• NRF2 is markedly downregulated in DPCs, hair follicle organoids, and DHT-induced mouse models under AGA-like conditions.
• Reduced NRF2 activity links to ferroptosis via SLC7A11–GSH–GPX4 suppression and increased lipid peroxidation.
• Concurrent features of disulfidptosis arise from impaired PPP activity, NADPH depletion, disulfide stress, and cytoskeletal disruption.
• Dimethyl fumarate-mediated NRF2 activation attenuates both ferroptosis and disulfidptosis, restoring hair follicle structure and promoting hair growth.

Clinical Implications

NRF2 activators (e.g., dimethyl fumarate) could be repurposed for AGA pending safety/efficacy trials. Biomarkers of ferroptosis/disulfidptosis may stratify patients or monitor response.

Limitations

• Preclinical study without human clinical trials
• Potential safety/off-target concerns of chronic NRF2 activation were not addressed

Future Directions

Translate NRF2 activation into early-phase AGA trials, develop biomarkers for ferroptosis/disulfidptosis in scalp biopsies, and compare NRF2 modulators for efficacy and safety.