Transcriptomic Analyses Predict Enhanced Metabolic Activity and Therapeutic Potential of mTOR Inhibitors in Acne-Prone Skin

Current acne therapies center on preventing new lesions in patients with acne. These therapies were historically found to be beneficial yet were chosen without knowledge of the specific changes in the skin that favor lesion development. A major challenge in developing new treatments is the incomplete understanding of nonlesional (NL), acne-prone skin’s molecular characteristics. To address this, we compared RNA-sequencing data from NL skin of 49 patients with acne (denoted as NL acne [NLA]) with those from 19 healthy controls with no acne history. We found 77 differentially expressed genes in NLA (log fold change > 1; P < .05), including genes associated with innate immunity and epidermal barrier function. Notably, KRT6C, KRT16, S100A8, S100A9, and lactotransferrin were upregulated, and LCE4A, LCE6A, and CTSE were downregulated. Gene set enrichment analysis revealed that metabolic pathways were enriched in NLA skin, whereas keratinization was negatively enriched. To identify compounds that could shift the gene expression signature of NLA skin toward healthy control skin, we performed connectivity mapping with the Library of Integrated Network-Based Signatures. We identified 187 compounds, particularly mTOR inhibitors, that could potentially normalize the gene expression profile of acne-prone skin to that of healthy skin. Our findings indicate that NLA skin has distinct differences in epidermal differentiation, cellular metabolism, and innate immunity that may promote lesion formation and suggest that mTOR inhibitors could restore NLA skin toward a healthier state, potentially reversing the predisposition to lesion development.