Modafinil Suppresses Hypertrophic Scar Formation by Inhibiting Adenosine Deaminase and Activating Adenosine Signaling

Modafinil (MF) is a clinically approved wake-promoting agent with emerging anti-inflammatory and anti-fibrotic effects, although its upstream molecular target has remained undefined. Here, we identify adenosine deaminase (ADA) as a previously unrecognized target mediating the therapeutic actions of MF. Its S- and R-isomers (MF-S and MF-R) robustly increased intracellular cAMP levels in fibroblasts with efficacy comparable to NECA, despite minimal direct binding to adenosine receptors, and suppressed KCa3.1 channel activity via a PKA–dependent mechanism. MF-S markedly upregulated CD39 and CD73, leading to increased adenosine availability. Pharmacological inhibition of CD73 with AB680 abolished MF-S–induced increases in cAMP and Epac levels and reversed suppression of TGFβ–induced collagen expression. Consistently, MF-S attenuated canonical profibrotic signaling by inhibiting TGFβ–induced Smad4 upregulation. In vivo, MF-S significantly reduced hypertrophic scarring in a rabbit ear model, with efficacy comparable to Contratubex. Mechanistically, MF-S directly inhibited purified ADA at subnanomolar concentrations and suppressed cellular ADA activity in fibroblast and immune cells. Collectively, these findings establish ADA inhibition as a key upstream mechanism by which MF enhances adenosine–cAMP signaling to suppress inflammation and fibrosis, highlighting MF and its isomers as promising therapeutic candidates for inflammatory and fibrotic diseases.