PLK1 inhibition by volasertib suppresses key transcriptional regulators underlying fibroblast activation and pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease marked by aberrant fibroblast activation, resulting in excessive proliferation, survival, and accumulation of extracellular matrix (ECM). A critical barrier to developing effective therapies for IPF is the limited understanding of druggable molecular regulators that control fibroblast activation. In this study, we identify the proto-oncogene MYCN as a key driver upregulated in dysregulated fibroblasts from IPF lungs. Mechanistically, we show that transforming growth factor α (TGFα) induces MYCN expression via the profibrotic transcription factor Wilms' tumor 1 (WT1). Notably, the knockdown of MYCN significantly attenuated fibroblast proliferation, survival, and ECM production. We further show that MYCN positively regulates the mitotic kinase, Polo-like kinase (PLK1), and that pharmacological inhibition of PLK1 using volasertib reduced expression of MYCN, WT1, and PLK1 and mitigated fibroblast activation. In vivo, volasertib treatment attenuated fibroblast activation and collagen deposition during TGFα-induced pulmonary fibrosis. Together, these findings identify a pathogenic role for the WT1-MYCN-PLK1 axis in fibroblast activation and provide proof-of-concept evidence supporting PLK1 inhibition with volasertib as a potential therapeutic strategy for IPF.NEW & NOTEWORTHY Excessive proliferation, impaired apoptotic clearance, and extracellular matrix (ECM) production are pathological features of fibroblast activation that together result in scar tissue formation in pulmonary fibrosis. This study identifies the previously unrecognized role for the WT1-MYCN-PLK1 axis in promoting fibroblast activation and highlights the therapeutic potential of PLK1 inhibition with volasertib as an antifibrotic strategy.