Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and invariably fatal interstitial lung disease driven by persistent alveolar epithelial injury, which triggers aberrant fibroblast activation and pathological myofibroblast differentiation. In this study, we identify CD147—a heavily glycosylated transmembrane protein of the immunoglobulin superfamily—as a novel glycosylation-dependent regulator of pulmonary fibrosis operating through dual mechanistic pathways. CD147 expression was markedly downregulated in fibrotic lung tissues and predominantly localized to pulmonary fibroblasts. CD147 depletion significantly enhances fibroblast activation, proliferation, and extracellular matrix (ECM) production. Mechanistically, CD147 promotes autophagosome formation and facilitates p62 degradation, indicating its function in augmenting autophagic clearance of pro-fibrotic effectors. Notably, the anti-fibrotic activity of CD147 is strictly contingent upon its N-linked glycosylation status, the fully glycosylated CD147 robustly suppresses fibroblast-to-myofibroblast transformation and ECM deposition, while non-glycosylated isoforms are entirely devoid of this regulatory capacity. These findings provide compelling evidence that CD147 enhancing autophagic clearance of pro-fibrotic effectors and suppress the fibrotic progression through glycosylation-dependent mechanisms.