Complement factor H drives idiopathic pulmonary fibrosis by autocrine C3 regulation, suppressing macrophage phagocytosis and enhancing fibrotic progression.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with limited therapeutic options. In this study, we identified Complement Factor H (CFH) as a critical regulator in the pathogenesis of IPF, contributing to fibrotic progression through autocrine regulation of complement component C3 and suppression of macrophage phagocytosis. Transcriptomic analysis of IPF lung tissues revealed upregulation of CFH and enrichment of pro-fibrotic pathways, including M2 macrophage infiltration. Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning further validated CFH as a key gene associated with macrophage polarization and fibrotic remodeling. Functional studies demonstrated that CFH deficiency in mouse models attenuated bleomycin-induced pulmonary fibrosis, as evidenced by reduced collagen deposition, improved lung function, and decreased macrophage infiltration. Mechanistically, CFH deficiency enhanced macrophage efferocytosis and autophagy, reducing macrophage-mediated inflammation and fibrosis. Moreover, siRNA-loaded liposomes targeting CFH mitigated pulmonary fibrosis in vivo, further supporting the therapeutic potential of CFH modulation. These findings highlight CFH as a promising therapeutic target for IPF and underscore the importance of complement regulation in macrophage-driven fibrosis.