Nanozyme Catalysis Restores Hair Follicle Integrity by Reversing Peroxisomal Collapse

Emerging evidence implicates organelle dysfunction, particularly within peroxisomes, as a critical driver of hair follicle degeneration and alopecia. While mitochondrial defects are well characterized in the context of hair loss, the contribution of peroxisomal failure to follicular homeostasis remains largely unexplored. Here, we identify peroxisomal dysfunction as a central molecular and metabolic defect underlying hair follicle aging and loss. Comprehensive transcriptomic analysis of human dermal papilla cells from alopecia patients revealed marked downregulation of peroxisome-associated pathways, including fatty acid β-oxidation, lipid degradation, and detoxification of reactive oxygen species. These alterations were recapitulated in <i>Nudt7</i>-deficient mice, in which targeted disruption of peroxisomal lipid metabolism leads to pronounced hair thinning, follicle miniaturization, and exacerbated oxidative stress. To therapeutically address peroxisomal impairment, we developed catalytic nanozymes (HA-Hem) that mimic peroxisomal catalase activity. Nanozyme treatment restored metabolic balance, reduced oxidative damage, and stimulated hair follicle regeneration in both wild-type and immunodeficient murine models. Mechanistically, nanozymes increased PPARα expression, thereby enhancing peroxisomal biogenesis and lipid metabolism. Elevated PPARα further improved peroxisome and mitochondrial function and strengthened peroxisome-mitochondria interactions, resulting in coordinated restoration of cellular redox and metabolic homeostasis. Compared with minoxidil treatment, nanozyme therapy produced greater regenerative responses and maintained therapeutic efficacy in immunodeficient settings. Spatial transcriptomic analysis further demonstrated an increased expression of keratin-associated proteins and cytoskeletal genes, consistent with activation of regenerative programs. These findings support a metabolism-focused therapeutic strategy targeting peroxisomal function in the treatment of alopecia.