Mapeo de conectividad con la firma transcriptómica de la isotretinoína identifica terapéuticas alternativas para el...

Isotretinoin, the gold-standard treatment for severe acne, effectively targets major pathogenic factors, but carries teratogenic risks. Its precise mechanism of action remains incompletely understood. Computational approaches, such as connectivity mapping, can offer insights into a drug's mechanism and identify alternative compounds as potential novel therapeutics for acne. In this study, we investigated the transcriptomic response in non-lesional skin of 18 severe acne patients prior to isotretinoin therapy (baseline) and after 1, 8, and 20 weeks of therapy and 6 months post therapy. Our analysis revealed that isotretinoin induced significant early and sustained suppression of metabolic pathways, including oxidative phosphorylation, lipid metabolism, and mTORC1 signaling. Immunofluorescence staining in acne patient skin for phospho-S6, a downstream marker of mTORC1, corroborated decreased mTORC1 signaling as early as 1-week of therapy. Additionally, connectivity mapping identified mTOR inhibitors as top candidates that mimic isotretinoin's transcriptomic signature. These findings enhance our understanding of isotretinoin's mechanism and highlight mTORC1 as a potential target for developing safer, non-teratogenic acne treatments.