PBK drives pulmonary fibrosis via activating p53/ACVR1C/Smad-mediated epithelial-mesenchymal transition.

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited therapeutic options. PDZ-binding kinase (PBK), also known as T-cell-originated protein kinase activated by lymphokines (TOPK), is implicated in cancer progression and inflammation, yet its role in fibrosis remains unexplored. This study aims to investigate PBK's contribution to PF pathogenesis and its underlying mechanisms. PBK was significantly upregulated in fibrotic lungs of bleomycin(BLM)-treated mice and PF patients, and its overexpression induced PF in vivo, marked by increased collagen synthesis, extracellular matrix (ECM) deposition, alveolar destruction, and epithelial-mesenchymal transition (EMT). Conversely, PBK knockdown attenuated BLM-driven fibrosis. RNA sequencing and biochemical assays confirm that PBK-driven epithelial-mesenchymal transition (EMT) and Smad activation are p53-dependent, as p53 inhibition rescues these effects. The authors delineate a signaling axis wherein PBK activates p53, which in turn modulates activin A receptor type 1C (ACVR1C) expression to enhance Smad3/4 signaling-a pathway central to EMT-driven fibrosis. These findings establish PBK as a regulator of PF pathogenesis via the PBK/p53/ACVR1C/Smad3/4 cascade, highlighting its potential as a therapeutic target.