Abstract

Androgenetic alopecia (AGA), a pervasive hair loss disorder, lacks effective therapies due to incomplete pathogenic understanding. Growing evidence suggests a connection between AGA and metabolic disorders. Leveraging unbiased serum metabolomics, a strikingly differentiated metabolic signature in AGA patients compared to healthy controls is identified, with arginine deficiency exhibiting the most pronounced reduction among all amino acids. Concomitant downregulation of the arginine transporter SLC7A1 and upregulation of arginine catabolic enzyme ARG2 in balding HFs are further identified, collectively driving localized arginine scarcity through impaired uptake and accelerated catabolism. This metabolic perturbation triggers pathological reactive oxygen species (ROS) accumulation in hair follicles (HFs), which, in turn, inhibits mTOR signaling and impairs HF regeneration. Conversely, arginine restoration via exogenous supplementation or inhibiting arginine-to-ornithine conversion with ARG2 siRNA rescues hair growth in both murine AGA model and cultured human HFs. Most importantly, a microneedle-based delivery system for targeted dermal arginine replenishment demonstrates robust therapeutic efficacy in humanized AGA models. This work establishes arginine insufficiency as a core pathogenic driver in AGA and validates localized metabolic correction as a promising clinical strategy.