<b>Leonurine (SCM198) alleviates pulmonary fibrosis through downregulation of the TGF-β1/Smad signaling pathway and activation of Nrf2-mediated antioxidant defenses during EMT</b>

<b>Background: </b>Idiopathic pulmonary fibrosis (PF) is a progressive lung disease characterized by activation of pulmonary fibroblasts and EMT in alveolar epithelial cells (AECs), largely driven by inflammation and oxidative stress (OS), leading to excessive extracellular matrix (ECM) deposition. Current treatments have limited efficacy and significant side effects. Leonurine and its sulfate derivative SCM198, from Herba Leonuri, exhibit anti-inflammatory and antioxidant properties; however, their therapeutic effects and mechanisms in PF remain unclear. <b>Methods: </b>PF was induced in mice by intratracheal bleomycin (BLM). HFL-1 fibroblasts and A549 AECs were exposed to TGF-β1 for in vitro assays. Effects of SCM198 on inflammation, ECM deposition, OS, and EMT were assessed in vivo and in vitro, with focus on TGF-β1/Smad2/3 and Keap1/Nrf2/HO-1 pathways. <b>Results: </b>SCM198 significantly improved lung pathology, micro-CT findings, and reduced collagen deposition in BLM-treated mice. Inflammatory markers and cytokines were lowered in lung tissue and BALF. In vitro, SCM198 inhibited fibroblast activation, EMT, and OS, downregulating TGF-β1/Smad2/3 and activating Nrf2 antioxidant pathways.<b>Conclusions:</b> SCM198 effectively alleviates BLM-induced PF, potentially by suppressing TGF-β1/Smad2/3 signaling and activating Nrf2-mediated antioxidant responses during EMT.<br>