Mapping fibroblast plasticity across non-cancer lung diseases at single-cell resolution

Fibroblast plasticity underlies a wide spectrum of pulmonary diseases, yet the molecular programs governing fibroblast state transitions in non-malignant contexts remain poorly understood. We integrated 1,470,730 single-cell transcriptomes across three non-cancer lung diseases to construct a comprehensive fibroblast atlas. Integrated clustering and regulon analyses were used to delineate fibroblast subtypes, disease-associated transcriptional programs, and state transitions. ANTXR1 , identified as a representative regulator, was validated by tissue immunohistochemistry and siRNA knockdown in primary lung fibroblasts under TGF-β stimulation. Compared with malignancy, fibroblasts in non-cancer lungs exhibited relatively modest transcriptional alterations but maintained distinct disease-associated phenotypes. We further identified a set of fibroblast-specific genes unique to non-malignant contexts, defining molecular features that distinguish fibrotic remodeling from tumor-associated stromal activation. Analysis of fibroblast subtype- and disease-specific regulons revealed 76 gene signatures that were significantly inversely correlated with lung function and distinguished chronic from acute fibrotic fibroblast states. Functional validation demonstrated that ANTXR1 knockdown markedly reduced COL1A1 expression, underscoring its role in fibroblast activation. This work establishes a comprehensive single-cell fibroblast atlas of non-cancer lung diseases, uncovering disease- and subtype-specific regulatory programs and highlighting potential therapeutic targets for fibrotic remodeling.