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Emerging evidence indicates that dysfunction of organelles, particularly in the peroxisomes, is a key driver of hair follicle degeneration and hair loss. Although mitochondrial defects have been well characterized in the context of hair loss, the contribution of peroxisome failure to the homeostasis of hair follicles remains largely unexplored. Here, we identify peroxisome dysfunction as the core molecular and metabolic defect underlying hair follicle aging and hair loss. Comprehensive transcriptomic analysis of human dermal papilla cells from patients with hair loss revealed that peroxisome-related pathways were significantly downregulated, including fatty acid β-oxidation, lipid degradation, and detoxification of reactive oxygen species. These changes were recapitulated in mice lacking Nudt7, where targeted interference targeting peroxisomal lipid metabolism led to significant hair thinning, miniaturization of hair follicles, and exacerbated oxidative stress. To treat peroxisome damage, we developed catalytic nanoenzymes (HA-Hem), mimicking the peroxisomal peroxidase activity. Nanoenzyme treatment restored metabolic balance, reduced oxidative damage, and stimulated hair follicle regeneration in wild-type and immunodeficient mouse models. Mechanistically, nanoenzymes increased PPARα expression, thereby enhancing peroxisomal biosynthesis and lipid metabolism. Increased PPARα further improved peroxisome and mitochondrial function, strengthened the interaction between peroxisomes and mitochondria, and coordinated the restoration of cellular redox and metabolic homeostasis. Compared to minoxidil treatment, nanoenzyme therapy produced a stronger regenerative response in an immunodeficient environment and maintained the therapeutic effect. Spatial transcriptomic analysis further revealed increased expression of keratin-related proteins and cytoskeletal genes, which is consistent with the activation of the regeneration program. These findings support a metabolic-oriented therapeutic strategy targeting peroxisome function for treating hair loss. This study was published in ACS Nano under the title "Nanozyme Catalysis Restores Hair Follicle Integrity by Reversing Peroxisomal Collapse".
Reference Information:
DOI: 10.1021/acsnano.5c1573
