Cinobufotalin Ameliorates the Development of Pulmonary Fibrosis by Suppressing the TGF‐β/Smad Pathway via Regulating PI15

Pulmonary fibrosis (PF) is a common hallmark of several types of interstitial lung diseases (ILDs), for which effective therapeutic drugs are lacking. The small‐molecule chemical compound cinobufotalin (CB) has demonstrated significant anti‐cancer effects in lung cancer. In this study, we first found that CB attenuated bleomycin (BLM)‐induced PF and inhibited transforming growth factor‐beta 1 (TGF‐β1)‐induced myofibroblast activation and epithelial‐mesenchymal transition (EMT). Subsequently, comparative RNA sequencing (RNA‐Seq) was conducted to analyse the lung gene expression profiles in mice. Interestingly, peptidase inhibitor 15 (PI15) was identified as a significantly differentially expressed gene (DEG) and may be a potential target in PF progression. Mechanistic studies showed that CB exerts anti‐PF effects by inhibiting PI15 and thereby regulating the TGF‐β/Smad signalling pathway. Our data demonstrated that CB represents a promising anti‐PF drug and may be a candidate therapeutic for PF patients.