Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease that is characterized by enhanced changes in stem cell differentiation and fibroblast proliferation. Lung resident mesenchymal stem cells (LR-MSCs) are important regulators of pathophysiological processes including tissue repair and inflammation, and evidence suggests that this cell population also plays an essential role in fibrosis. Our previous study demonstrated that Wnt/β-catenin signaling is aberrantly activated in the lungs of bleomycin-treated mice and induces myofibroblast differentiation of LR-MSCs. However, the underlying correlation between LR-MSCs and the Wnt/β-catenin signaling remains poorly understood. We found that Wnt8b was highly expressed by LR-MSCs undergoing myofibroblast differentiation. In vitro, Wnt8b promoted LR-MSCs differentiate into myofibroblasts via activating Wnt/β-catenin signaling. Moreover, siRNA-mediated inhibition of Wnt8b prevented Transforming growth factor (TGF)-β1-induced myofibroblast differentiation of LR-MSCs in vitro and ameliorated pulmonary fibrotic lesions. Our study identified Wnt proteins and Wnt/β-catenin signaling in pulmonary fibrosis in vitro and in vivo, and highlighted Wnt8b as a potential therapeutic target in pulmonary fibrosis. Moreover, these finding might provide a new perspective in the development of treatment strategies for IPF.

Pulmonary fibrosis is driven by persistent fibroblast activation and extracellular matrix (ECM) accumulation, yet upstream regulators that initiate and sustain these programs remain incompletely defined. Here, we tested whether the ribosomal S6 kinase 1-serum response factor (RSK1-SRF) axis contributes to idiopathic pulmonary fibrosis (IPF) and represents a tractable therapeutic target. Mendelian randomization supported a causal association between RSK1 and IPF risk, which aligned with increased RSK1 activity in human IPF lungs and bleomycin-injured mice. In lung fibroblasts, pharmacologic RSK1 inhibition blunted TGF-β-induced fibroblast-to-myofibroblast transition and ECM production. Mechanistically, RSK1 associated with SRF and promoted SRF phosphorylation and activation, thereby enhancing SRF-dependent profibrotic transcription. In vivo, perturbation of the RSK1-SRF axis attenuated fibroblast activation, ECM deposition, and histologic fibrosis. Collectively, these findings indicate RSK1 as a druggable upstream driver of SRF-dependent profibrotic programs and motivate further evaluation of RSK1-directed strategies for IPF.