PHB2 acts as a braker of progressive pulmonary fibrosis via intervention of DDR2-elicited signaling

Idiopathic pulmonary fibrosis (IPF) is a fatal disease whose pathogenic mechanisms remain incompletely understood. Transforming growth factor-beta (TGF-β) is widely regarded as a central driver of fibrosis, orchestrating sustained fibroblast activation and pathological tissue scarring. DDR2 (discoidin domain receptor tyrosine kinase 2), a discoidin domain receptor tyrosine kinase, serves as a critical mediator of non-canonical TGF-β1 signaling. Using lung samples from patients with IPF, human precision-cut lung slices (PCLS), primary lung fibroblasts and a BLM (bleomycin)-induced mouse model, we investigate the role of prohibitin 2 (PHB2) in fibrotic progression. Here, we demonstrate that PHB2 binds to DDR2 and suppresses collagen I-induced DDR2 tyrosine phosphorylation, as well as TGF-β1-stimulated activation of ERK, p38, AKT and Smad-3, leading to downregulation of key fibrotic markers. Accordingly, AAV9-mediated PHB2 overexpression exhibits therapeutic effects in a mouse model of pulmonary fibrosis. We also observe significant downregulation of PHB2 in IPF lungs. Functionally, PHB2 attenuates fibroblast migration and counteracts the TGF-β1-induced enhancement of mitochondrial respiration in lung fibroblasts. Mechanistically, PHB2 disrupts the interaction between DDR2 and TGF-β receptor II (TGFBR2) and inhibits DDR2 phosphorylation, thereby mitigating fibrotic responses in fibroblasts and PCLS- and BLM-induced mouse models. Our findings indicate that PHB2 acts as a molecular "braker" of both TGF-β1- and DDR2-driven profibrotic pathways in pathogenic fibroblasts.