Alopecia areata (AA) is an autoimmune disorder characterized by oxidative stress-induced dysfunction of hair follicle stem cells (HFSCs). Nicotinamide mononucleotide (NMN), a precursor of NAD+, exhibits antioxidant properties, but its role and mechanism in AA remain unclear. This study aimed to investigate the therapeutic potential of NMN and its underlying mechanism. Scalp tissues from AA patients and healthy controls were collected, and HFSCs were isolated. An in vitro oxidative stress model was established using H2O2. Cell viability, apoptosis, migration, oxidative stress and glutamine metabolism were assessed. Molecular mechanisms were investigated via gene knockdown (sh-SIRT7, sh-GLS1) and rescue experiments with an acetylation-resistant GLS1 mutant (GLS1-MUT). An in vivo mouse model of H2O2-induced hair follicle damage was utilized for validation. The results showed that NMN (2 mM) significantly enhanced the viability, migration, and differentiation capacity of both AA-derived and H2O2-induced HFSCs, while cell apoptosis and oxidative stress were repressed. NMN also promoted glutamine metabolism with increased GSH, glutamate, glutamine and NAD+ levels, as well as elevated GPx and GLS1 activities. Mechanistically, SIRT7 expression was downregulated in AA. NMN restored SIRT7 expression and activity, leading to the deacetylation and activation of GLS1. Knockdown of SIRT7 or GLS1 abolished NMN's protective effects, which were rescued by GLS1-MUT, establishing a linear pathway. In vivo, NMN treatment alleviated H2O2-induced hair follicle damage, promoted regeneration, and preserved SIRT7 expression in the stem cell niche. In conclusion, NMN alleviates oxidative stress and improves HFSC function in AA by activating the SIRT7-GLS1 axis and enhancing glutamine metabolism, revealing a novel therapeutic target for AA.
