Inhalable Carbonyl\nSulfide Donor-Hybridized Selective\nPhosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary\nFibrosis by Inhibiting Tumor Growth Factor‑β Signaling\nand Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding\

Idiopathic\npulmonary fibrosis (IPF) is a debilitating,\nincurable,\nand life-threatening disease that lacks effective therapy. The overexpression\nof phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary\nfibrosis (PF). However, the impact of selective PDE10A inhibitors\non the tumor growth factor-β (TGF-β)/small mother against\ndecapentaplegic (Smad) signaling pathway remains unclear. Herein,\nwe have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide\n(H<sub>2</sub>S)-donor hybrid PDE10A inhibitor called <b>COS-2080</b> with a well-defined mechanism of H<sub>2</sub>S-releasing action.\nIt exhibited highly potent inhibitory activity against PDE10A and\nexcellent PDE subfamily selectivity. Moreover, <b>COS-2080</b> demonstrated significant antifibrotic effects by inhibiting cell\nproliferation and mitigating fibroblast-to-myofibroblast transition\n(FMT). A dry powder inhalation formulation called <b>COS-2080-DPI</b> has been developed using the ultrasonic spray freeze drying (USFD)\ntechnique, demonstrating significant antifibrotic efficacy in mice\nwith bleomycin-induced PF at a dosage approximately 600 times lower\nthan pirfenidone. This remarkable antifibrotic efficacy of <b>COS-2080</b> on TGF-β1-induced FMT could be primarily attributed to its\ninhibition of the Smad2/Smad3 phosphorylation. Moreover, <b>COS-2080</b> effectively attenuated fibrosis in MRC-5 cells by activating the\ncAMP/protein kinase A (PKA)/CREB pathway and potentially increasing\nlevels of p53 protein. Our findings suggest that effective inhibition\nof PDE10A potentially confers a protective effect on FMT in PF by\nimpeding TGF-β signaling and activating the cAMP/PKA/CREB/p53\naxis.