Mechanistic Investigation of Five Small-Molecule Inhibitors in the Treatment of Pemphigus Vulgaris via RNA-Seq Analysis

Pemphigus vulgaris (PV) is an autoimmune disorder characterized by autoantibodies (AAbs) against Desmoglein 1 (DSG1) and Desmoglein 3 (DSG3) on keratinocytes, resulting in compromised cell-cell adhesion and epidermal blistering. To explore potential therapeutic targets, five small-molecule inhibitors, A66 (PI3Kα inhibitor), BIRB796 (p38 MAPK inhibitor), GW441756 (TrkA inhibitor), Selumetinib (MEK1 inhibitor), and Vandetanib (VEGFR2 inhibitor) were selected through a screen identifying compounds that reduce split formation in a human skin organ culture (HSOC) model. Each inhibitor exhibits distinct transcriptomic profiles that contribute to gene expression modulation, yet all share a common downregulation of chemokine signaling pathways associated with split formation. These inhibitors, capable of mitigating skin blistering in PV, present potential as therapeutic agents for this challenging autoimmune condition. Human skin samples were treated by injection with anti-Dsg1/3 scFv without the addition of pemphigus vulgaris (PV) antibodies (negative control, NC), with PV antibodies alone (positive control, PC), or with PV antibodies in the presence of the indicated inhibitors (A66, BIRB796, GW441756, Selumetinib, and Vandetanib). After 24 hours of culture, samples were subjected to RNA-Seq analysis to assess transcriptomic changes associated with each treatment condition.