Mechanistic Insights into Vorinostat as a Repositioned Modulator of TACE-Mediated TNF-α Signaling via MAPK and NFκB Pathways

Vorinostat, an FDA-approved histone deacetylase inhibitor, was evaluated for its potential anti-inflammatory activity through modulation of TACE (ADAM17)-mediated TNF-α signaling. The study was conducted using LPS-stimulated RAW264.7 macrophages. TACE enzymatic activity was assessed by a fluorogenic assay, TNF-α release was measured by ELISA, and phosphorylation of MAPKs and NFκB signaling proteins was examined by a western blot. Molecular docking was performed using GNINA to evaluate binding affinity to ERK. Vorinostat was found to modestly inhibit TACE enzymatic activity in vitro, while significantly suppressing TNF-α secretion in cells, comparable to the selective TACE inhibitor BMS-561392. A concentration-dependent reduction in phosphorylated IκB and NFκB was observed, along with selective inhibition of ERK phosphorylation. Docking studies indicated a stable, albeit weaker, binding of vorinostat to ERK compared to reference ERK inhibitors. These findings suggest that vorinostat suppresses TNF-α production primarily through indirect mechanisms involving ERK and NF-κB signaling pathways, rather than by direct TACE inhibition. The repositioning of vorinostat as a modulator of inflammatory signaling is supported, offering potential therapeutic value in inflammatory disorders.