NRF2 coordinates ferroptosis and disulfidptosis in dermal papilla cells via redox metabolic reprogramming in androgenetic alopecia.

Dysfunction of dermal papilla cells (DPCs) is a central feature of androgenetic alopecia (AGA), in which oxidative imbalance plays a critical role. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular redox homeostasis; however, its role in AGA remains unclear. Here, using primary DPCs, hair follicle organoids, and dihydrotestosterone (DHT)-induced mouse models, we found that NRF2 was markedly downregulated under AGA-associated conditions. Mechanistically, our data suggest that reduced NRF2 activity is associated with two distinct regulated cell death-related processes in DPCs: ferroptosis and disulfidptosis. Pharmacological activation of NRF2 by dimethyl fumarate (DMF), together with molecular and metabolic analyses, indicated that impaired NRF2 signaling was linked to suppression of the SLC7A11-GSH-GPX4 axis, increased lipid peroxidation, and ferroptosis-related injury. In parallel, reduced NRF2 activity was associated with impaired pentose phosphate pathway (PPP) activity, NADPH depletion, disulfide stress, cytoskeletal disruption, and features consistent with disulfidptosis. Pharmacological activation of NRF2 by dimethyl fumarate (DMF) effectively attenuates both ferroptosis and disulfidptosis, restoring hair follicle structure and promoting hair growth in AGA models. Collectively, our findings identify NRF2 as a central regulator linking redox metabolism to ferroptosis and disulfidptosis in DPCs, and highlight NRF2 activation as a potential therapeutic strategy for AGA.