Exploring the Efficacy and Potential Mechanisms of Topical Periplaneta americana (L.) Extract in Treating Androgenetic Alopecia in a Mouse Model: A Systems Pharmacology and Skin Microbiome Analysis

Androgenetic alopecia (AGA), the most prevalent form of hair loss, faces challenges such as high costs and limited efficacy in current treatments. This study demonstrates that PA-011, a derivative of Periplaneta americana (L.), exhibits promising therapeutic potential in AGA mouse models. Using a DHT-induced AGA mouse model combined with multi-omics approaches (LC-MS/MS, transcriptomics, metabolomics) and 16S rRNA microbiome analysis, we found that PA-011 promotes hair follicle stem cell proliferation (via upregulated Ki67 expression) by activating the Wnt/β-catenin pathway while suppressing oxidative stress and inflammation. Mechanistic studies revealed its ability to regulate the PI3K-Akt/MAPK signaling pathways, improve pentose phosphate metabolism and amino acid biosynthesis, and maintain skin microbial homeostasis. Safety assessments confirmed no toxicity with topical application. This preclinical study highlights PA-011 as a multi-target therapeutic candidate for AGA, offering a novel strategy for future treatment development. Androgenetic alopecia (AGA), the most prevalent form of hair loss worldwide, faces significant therapeutic challenges due to high costs and limited efficacy of current interventions, necessitating safer and more effective solutions. Periplaneta americana (L.)-derived PA-011, endowed with anti-inflammatory and antioxidant properties, has demonstrated notable hair growth-promoting effects in AGA mouse models. This study employed LC-MS/MS, peptidomics, and network pharmacology to characterize PA-011’s chemical composition and predict its potential targets in AGA pathogenesis. Using Western blot and RT-qPCR, PA-011 intervention significantly inhibited inflammatory responses and oxidative stress levels in mouse skin tissues. Concurrently, PA-011 activated the proliferative potential of hair follicle stem cells, as demonstrated by upregulated expression of the cell proliferation marker Ki67, and activated the Wnt/β-catenin signaling pathway in DHT-induced AGA mice. Transcriptomic and metabolomic analyses revealed multi-target effects of PA-011, including modulation of PI3K-Akt/MAPK pathways, pentose phosphate metabolism, and amino acid biosynthesis. 16S rRNA sequencing and metagenomic analysis showed that AGA disrupts skin microbial homeostasis, while PA-011 intervention normalized the microbiota composition. Topical application of PA-011 promoted robust hair regrowth without detectable toxicity in safety assessments. This preclinical study establishes PA-011 as a promising candidate for AGA therapy, warranting further translational investigation.