Solriamfetol Suppresses Inflammation and Fibrosis via Adenosine Deaminase Inhibition in a Murine Model of an Idiopathic Pulmonary Fibrotic Disease

Background: Solriamfetol, a dopamine and norepinephrine reuptake inhibitor widely used in narcolepsy management, has not been thoroughly investigated for its anti-fibrotic and anti-inflammatory properties. Herein, we investigated its potential therapeutic applications and underlying mechanisms in both cellular and murine models of pulmonary fibrosis. Methods: To induce fibrosis, C57BL/6 male mice (six-week-old) were administered bleomycin via the intratracheal route. These animals subsequently received solriamfetol orally once per day at dosages of 3 or 10 mg/kg. Histological and immunohistochemical techniques were employed to evaluate inflammatory cell infiltration, collagen accumulation, and α-smooth muscle actin (α-SMA) expression in bronchoalveolar lavage samples and lung tissue sections. Cytokine levels were measured by ELISA, and gene/protein expression of pro-fibrotic markers, A2A/A2B adenosine receptors (ARs), adenylate cyclases (ACs), Epac, KCa3.1, and adenosine deaminase (ADA) were assessed via quantitative PCR and Western blot. Electrophysiological recordings evaluated KCa3.1 channel activity. Purified ADA and normal human lung fibroblasts (NHLFs) were treated with solriamfetol to assess effects on ADA activity and levels of cAMP and adenosine, respectively. Results: Solriamfetol significantly reduced inflammatory cell infiltration, collagen accumulation, and α-SMA expression in fibrotic lungs. Solriamfetol restored downregulated A2AAR, A2BAR, ACs, and Epac, while suppressing ADA expression and activity, resulting in elevated extracellular adenosine and intracellular cAMP. The intervention potentiated Epac signaling and inhibited fibroblast activation. Solriamfetol inhibited the KCa3.1 current in fibroblasts and reduced KCa3.1 protein expression levels in TGFβ-treated fibroblasts and lung tissues from bleomycin-challenged mice. Notably, these effects were abolished by A2AAR or A2BAR antagonists, implying that they occur through AR-mediated pathways. Conclusions: Solriamfetol inhibits ADA and reinforces adenosine–cAMP signaling, suppressing pathological fibroblast activation. These findings suggest its therapeutic utility as a novel anti-fibrotic compound for various fibrotic diseases, including pulmonary fibrosis.