SOX8 Promotes Fibroblast Activation and Fibrotic Progression Through ANTXR1‑Mediated GLI1 Upregulation in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by fibroblast activation and collagen deposition. While ANTXR1 is a transmembrane protein implicated in various pathologies including lung cancer, its specific expression patterns and molecular mechanisms within the context of IPF remain elusive. In this study, we show that ANTXR1 expression is markedly elevated in IPF lung tissues, in bleomycin (BLM)-induced pulmonary fibrosis mouse models, and in TGF-β1-stimulated fibroblasts. Functionally, ANTXR1 was found to drive the proliferation and differentiation of TGF-β1-treated human and mouse fibroblasts. Mechanistically, in TGF-β1-treated fibroblasts, we identified that the transcription factor SOX8 directly binds to the ANTXR1 promoter to transcriptionally activate its expression. Furthermore, ANTXR1 promotes IPF progression by upregulating GLI1, a critical downstream effector of the Hedgehog signaling pathway. Therapeutically, intratracheal delivery of Antxr1-targeting shRNA via adeno-associated virus (AAV) significantly ameliorated the fibrotic phenotype in BLM-induced mice. Our findings suggest that SOX8 drives fibroblast activation and fibrotic progression in idiopathic pulmonary fibrosis by elevating GLI1 expression via ANTXR1, and identify ANTXR1 as a promising therapeutic target for IPF.