Gentamicin and Citronella-Derived Compounds as Dual Modulators of Inflammation-Associated Targets in Acne Vulgaris

Acne Vulgaris is a chronic inflammatory skin disorder driven by a combination of microbial colonization, immune dysregulation, and disruption of the epidermal barrier. Although isotretinoin remains the most effective treatment, the molecular mechanisms underlying its anti-inflammatory effects are incompletely understood. This study integrates transcriptomic meta-analysis and computational drug screening to identify novel therapeutic targets and candidate compounds for acne management. Three publicly available GEO datasets (GSE6475, GSE10433, GSE11792) were analyzed to identify differentially expressed genes (DEGs) associated with isotretinoin response. Among these, Spectrin beta, non-erythrocytic 1 (SPTBN1) and Signal-induced proliferation-associated 1-like protein 1 (SIPA1L1) emerged as consistently regulated genes with known roles in cytoskeletal organization and immune signaling, respectively. To assess the druggability of these targets, molecular docking was conducted using gentamicin and natural compounds derived from Cymbopogon winterianus, including citronellol, citral, citronellal, and geraniol. Gentamicin demonstrated the strongest binding affinity to SIPA1L1 (-8.6 kcal/mol) and SPTBN1 (-5.9 kcal/mol), forming multiple hydrogen bonds and hydrophobic contacts. Subsequent 100 ns molecular dynamics (MD) simulations confirmed the stability of the gentamicin-protein complexes, as evidenced by favorable RMSD, RMSF, and energy profiles. Interaction energy decomposition revealed strong contributions from electrostatic and van der Waals forces. These findings highlight the potential of gentamicin, and possibly structurally related natural compounds, as modulators of host inflammatory pathways implicated in acne. The study further underscores the utility of integrating transcriptomics, molecular docking, and MD simulation for early-phase therapeutic discovery targeting inflammation and barrier dysfunction in dermatological diseases.