Transcription factor ID3 promotes fibroblast differentiation and proliferation in lung fibrosis through augmenting...

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by myofibroblast activation, accumulation, and excessive extracellular matrix deposition. Although fibroblast activation and proliferation are central drivers of fibrogenesis, the molecular regulators coordinating these processes remain poorly defined. This study investigated fibroblast lineage progression using single-cell RNA-sequencing data from fibroblast-enriched populations in bleomycin-induced mouse models and human IPF samples. In mice, TGF-β signaling was significantly enriched in both activated and proliferative fibroblast subsets. ID3 was identified as a key transcriptional regulator, whose expression closely correlated with augmented TGF-β signaling. Gene regulatory network analysis further suggested that ID3 modulates TGF-β-dependent profibrotic programs. In human IPF, a homologous ID3-high fibroblast population with high proliferative potential was identified, in which ID3 activity was strongly associated with TGF-β signaling. Together, these findings indicate that ID3 promotes fibroblast differentiation and proliferation through the TGF-β signaling pathway, highlighting ID3 as a potential regulator of profibrotic fibroblast progression.