ZNF469 promotes human lung fibrosis via transcriptionally regulating extracellular matrix genes

Pulmonary fibrosis (PF) is a chronic lung disease defined by excessive deposition of extracellular matrix (ECM) components, leading to remodeling of lung structural architerture and impaired repiratory function. Chronically activated resident fibroblasts are considered one of major cellular source of aberrant ECM accumulation; however, their precise cellular origins and the initiating events that drive their persistent activation remain incompletely understood. Emerging evidence has identified zinc finger protein 469 (ZNF469) as a novel pro-fibrotic transcription factor in hepatic stellate cells and dermal fibroblasts, where it drives ECM gene expression and fibrogenic remodeling, suggesting a potentially conserved role across fibrotic tissues. With short hairpin-mediated doxycycline inducible system, ZNF469 knockdown LFs are employed to explore its ficbrotic potential in LFs. Depletion of ZNF469 resulted in marked impairment of LF proliferation and migratory capacity, accompanied by reduced collagen production and secretion. Transcriptomic profiling further revealed significant downregulation of ECM-associated pathways following ZNF469 knockdown, supporting a conserved role for ZNF469 in fibroblast-driven fibrogenesis. Consistently, CUT&RUN analysis demonstrated direct binding of ZNF469 to the promoters of a broad spectrum of ECM-related genes in LFs. Collectively, these findings uncover a previously unrecognized regulatory role of ZNF469 as a key pro-fibrotic transcription factor in lung fibroblasts and highlight its potential as a promising therapeutic target for pulmonary fibrosis.