Bufotalin attenuates pulmonary fibrosis via inhibiting Akt/GSK-3β/β-catenin signaling pathway

• DOI: 10.1016/j.ejphar.2023.176293
• Publication Date: 2023-12-27T16:30:26Z
• Authors: Ji-zhong Yin; Zhu-qing Li; Xi-de Zhang; Zhi-jie Wan; Hong-ran Qin; Liu-huan Yao; Bai-long Li; Fu Gao; Yan-yong Yang
• Keywords: Transforming Growth Factor beta1; Bufanolides; Bleomycin; Glycogen Synthase Kinase 3 beta; Epithelial-Mesenchymal Transition; Humans; Proto-Oncogene Proteins c-akt; Wnt Signaling Pathway; beta Catenin; Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with no cure. Bufotalin (BT), an active component extracted from Venenum Bufonis, has been prescribed as a treatment for chronic inflammatory diseases. However, whether BT has antifibrotic properties has never been investigated. In this study, we report on the potential therapeutic effect and mechanism of BT on IPF. BT was shown to attenuate lung injury, inflammation, and fibrosis as well as preserve pulmonary function in bleomycin (BLM)-induced pulmonary fibrosis model. We next confirmed BT's ability to inhibit TGF-β1-induced epithelial-mesenchymal transition (EMT) and myofibroblast activation (including differentiation, proliferation, migration, and extracellular matrix production) in vitro. Furthermore, transcriptional profile analysis indicated the Wnt signaling pathway as a potential target of BT. Mechanistically, BT effectively prevented β-catenin from translocating into the nucleus to activate transcription of profibrotic genes. This was achieved by blunting TGF-β1-induced increases in phosphorylated Akt Ser437 (p-Akt S437) and phosphorylated glycogen synthase kinase (GSK)-3β Ser9 (p-GSK-3β S9), thereby reactivating GSK-3β. Additionally, the antifibrotic effects of BT were further validated in another in vivo model of radiation-induced pulmonary fibrosis. Collectively, these data demonstrated the potent antifibrotic actions of BT through inhibition of Akt/GSK-3β/β-catenin axis downstream of TGF-β1. Thus, BT could be a potential option to be further explored in IPF treatment.