Targeting PBK in the fibroblast-to-myofibroblast transition: A novel therapeutic strategy for IPF

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown etiology with poor prognosis and limited therapies. OTS514, a PBK inhibitor, has been implicated in suppressing tumor progression by modulating various cellular biological processes. Nonetheless, the potential impact of PBK and OTS514 on IPF have yet to be elucidated. PBK expression and distribution in IPF and control lung tissues were analyzed by Western blot, RT-PCR, and immunofluorescence. Then, the bleomycin (BLM) -induced mouse model and human precision-cut lung slices (HPCLS) were utilized to detect the antifibrotic effects of the OTS514. Primary lung fibroblasts derived from both control and IPF patients were further employed to uncover the underlying mechanisms of PBK. Our study demonstrated that PBK expression was markedly elevated in IPF patients and exhibited a negative correlation with lung function. Remarkably, the administration of OTS514 significantly mitigated Collagen deposition and lung tissue remodeling in the BLM-induced mouse model. Additionally, OTS514 also exserted a pronounced antifibrotic effect in HPCLS, as evident by downregulation of fibrotic related markers expression (α-SMA, Collagen 1 and Fibronectin) and pathological manifestations. In vitro experiments demonstrated that the inhibition of PBK suppressed fibroblast differentiation and migratory capacity, reduced the proliferation rate, and promoted Apoptosis. Mechanically, we discovered that the protective effect of OTS514 in vivo and vitro was closely dependent upon the endoplasmic reticulum stress pathways. Collectively, our data underscores the potential of OTS514 as an antifibrotic strategy by attenuating fibroblast-to-myofibroblast transition. Furthermore, the administration of OTS514 manifested no adverse effects in mouse model.

Endoplasmic reticulum stress; Fibroblast; Idiopathic pulmonary fibrosis; OTS514; PBK.