BI-2536 attenuates IPF progression by inhibiting the PLK2/JNK/SP1 Signaling pathway in AT2 cells.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal pulmonary disorder with limited effective therapeutic options. In this study, differential gene expression analysis of lung tissues from IPF patients and alveolar type 2 (AT2) cells identified BI-2536 as a potential therapeutic candidate for IPF. In an in vivo model, BI-2536 significantly ameliorated bleomycin (BLM)-induced pulmonary function decline in IPF mice while suppressing pulmonary inflammation and fibrosis markers, thereby mitigating pathological lung tissue damage. Further investigations revealed that polo-like kinase 2 (PLK2) serves as a key target of BI-2536, with Gly92 identified as a critical binding residue. Mechanistically, BI-2536 binds to PLK2, inhibiting downstream phosphorylation of JNK1/2 and SP1, consequently suppressing BLM-induced epithelial-mesenchymal transition (EMT) and fibrotic progression in AT2 cells. In summary, this study demonstrates that BI-2536 delays IPF progression by inhibiting the PLK2/JNK/SP1 signaling pathway in AT2 cells, providing a novel therapeutic agent and target for pulmonary fibrosis treatment.