PTPN1 Regulation via YBX1-PTBP1 Interaction Promotes Fibroblast Activation and Fibrotic Remodeling in the Lung

TL;DR

This study shows how YBX1 promotes lung fibrosis by interacting with PTBP1 and regulating PTPN1, offering new therapeutic insights for idiopathic pulmonary fibrosis.

Contribution

The novel contribution is identifying YBX1's role in promoting fibroblast activation via the PTBP1/PTPN1 axis in lung fibrosis.

Findings

YBX1 overexpression enhances TGF-β1-induced fibroblast activation and ECM deposition.

YBX1 interacts with PTBP1 and regulates PTPN1 transcription to drive fibroblast-to-myofibroblast transition.

AAV-delivered Ybx1 shRNA reduces fibrosis markers in a murine model of lung fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial pneumonia of unknown etiology. Its pathogenesis involves complex multicellular interactions and signaling pathways, with fibroblast-to-myofibroblast transition (FMT) being critical for fibrogenesis. Although the transcription factor Y-box binding protein 1 (YBX1) regulates processes such as cell proliferation, transcription, translation, and DNA repair, its role in IPF remains undefined. Here, we demonstrate that YBX1 overexpression significantly promotes transforming growth factor-β1 (TGF-β1)-induced pulmonary FMT, leading to substantially increased extracellular matrix (ECM) deposition in primary human (PHLFs) and mouse (PMLFs) lung fibroblasts. Conversely, YBX1 inhibition markedly suppresses TGF-β1-driven aberrant fibroblast migration and activation. Mechanistically, YBX1 interacts with polypyrimidine tract-binding protein 1 (PTBP1) and binds to the protein tyrosine phosphatase nonreceptor type 1 (PTPN1) promoter to transcriptionally regulate PTPN1, thereby driving FMT. In vivo, intratracheal delivery of Ybx1-targeting shRNA via adeno-associated virus (AAV) robustly attenuates ECM deposition, hydroxyproline content, and fibrotic marker expression in a bleomycin (BLM)-induced murine fibrosis model. Our findings identify YBX1 as a promoter of lung FMT via the PTBP1/PTPN1 axis, offering mechanistic insights for the development of YBX1-targeted therapeutic strategies for IPF.

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