Connectivity mapping with isotretinoin’s transcriptomic signature identifies alternative therapeutics for severe acne

Summary: Abstract Body: Isotretinoin, the gold-standard treatment for severe acne, effectively targets key pathogenic factors but carries teratogenic risks, and its precise mechanism of action remains incompletely understood. Computational approaches, such as connectivity mapping, can help elucidate drug mechanisms and identify alternative therapeutic candidates. In this study, we performed RNA-sequencing to investigate the transcriptome of non-lesional whole skin from the upper back of 18 severe acne patients (IGA acne score: 3-4) at baseline and after 1, 8, and 20 weeks of isotretinoin therapy. Gene set enrichment analysis (GSEA) revealed consistent negative enrichment of pathways related to oxidative phosphorylation, adipogenesis, fatty acid metabolism, cholesterol homeostasis, bile acid metabolism, and mTORC1 signaling across all timepoints, indicating sustained suppression of metabolic and lipid pathways. These findings align with isotretinoin’s known effects on sebum production. Immunofluorescence staining of matched tissue sections for phospho-S6, a downstream marker of mTORC1 activity, demonstrated reduced staining intensity in sebaceous glands at 1 week compared to baseline, corroborating the GSEA findings of reduced mTORC1 signaling. Connectivity mapping of the 1-week isotretinoin transcriptomic signature using the chemical perturbagen signatures from the Library of Integrated Network-based Cell Signatures (LINCS) resource identified mTOR inhibitors as top candidates that mimic isotretinoin’s effects. These results provide new insights into isotretinoin’s mechanism of action and highlight mTORC1 as a promising target for the development of safer, non-teratogenic therapies for severe acne. Mackenzie L. Sennett^{1, 2}, Robert Feehan¹, Zhaoyuan Cong¹, Tierney Wallace¹, Amy Longenecker¹, Andrea Zaenglein¹, Diane Thiboutot¹, Amanda M. Nelson¹ 1. Dermatology, Penn State College of Medicine, Hershey, PA, United States. 2. MD/PhD Program, Penn State College of Medicine, Hershey, PA, United States. Bioinformatics, Computational Biology, and Imaging