Obacunone Targets Serine–Threonine Kinase Receptor–Associated Protein to Promote the Formation of the TGF‐β/Smad7 Complex and Ameliorates Bleomycin‐Induced Pulmonary Fibrosis

ABSTRACT Pulmonary fibrosis (PF) is a complex and fatal interstitial lung disease in which the TGF‐β/Smad signaling pathway plays a pivotal role in fibrotic progression. However, strategies for precise modulation of this pathway remain limited. In this study, a bleomycin (BLM)‐induced mouse model of PF and TGF‐β‐stimulated MLE‐12 or primary lung fibroblast models were used to investigate the antifibrotic effects and underlying mechanisms of obacunone (OB). OB markedly attenuated PF progression, reduced collagen deposition and hydroxyproline (HYP) levels, and inhibited wound healing and migration capacities of TGF‐β‐stimulated MLE‐12 cells and fibroblasts. Surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), molecular docking, and molecular dynamics simulations identified a direct binding interaction between OB and serine–threonine kinase receptor–associated protein (STRAP). Furthermore, co‐immunoprecipitation (Co‐IP) and immunofluorescence analyses confirmed that OB promoted the formation of the STRAP–TGF‐βR II/Smad7 complex, thereby suppressing activation of the TGF‐β/Smad2/3 pathway. Collectively, this study is the first to demonstrate that OB ameliorates PF by targeting STRAP to modulate the TGF‐β/Smad2/3 signaling cascade, providing new evidence for the antifibrotic mechanism of OB and supporting STRAP as a potential therapeutic target for PF intervention.