Single-cell and spatial transcriptomics reveal that idiopathic pulmonary fibrosis is driven by a complex communication network among multiple cell compartments rather than a single cell type.
Single-cell and spatial transcriptomics reframe idiopathic pulmonary fibrosis as a disease of a maladaptive cellular communication network, suggesting future therapies should target specific niche communication axes.
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease driven by aberrant repair after repetitive alveolar micro-injury. The classical paradigm — that fibrosis is a passive consequence of epithelial injury followed by fibroblast activation — has been substantially reshaped by single-cell RNA sequencing (scRNA-seq) and, more recently, spatial transcriptomics. These technologies have resolved the lung into a constellation of molecularly distinct cell states and exposed a highly structured fibrotic niche in which epithelial, mesenchymal, immune, and endothelial compartments are engaged in active, ligand–receptor–mediated crosstalk. This review synthesizes the emerging single-cell and spatial atlas of human PF/ILD, with a focus on four themes: (i) the ectopic KRT5⁻/KRT17⁺ aberrant basaloid epithelium and the persistence of a KRT8⁺ alveolar differentiation intermediate ; (ii) the lipofibroblast-to-myofibroblast trajectory and the collagen-producing fibroblast atlas that explains heterogeneous drug response; (iii) immune remodeling , particularly the metabolic reprogramming of SPP1⁺/MERTK⁺ macrophages and the exhaustion of CD8⁺ T cells; and (iv) the spatial organization of disease-associated niches at the fibroblast-focus edge. We then translate these findings into a framework for molecular subtyping and precision medicine , arguing that the future of IPF therapy lies in disrupting specific niche communication axes rather than broadly antagonizing collagen synthesis. Beyond cataloguing cell types, we emphasize the systems-level principle that emerges from the single-cell literature: IPF is not a disease of one cell type gone wrong, but a disease of the communication network that binds multiple compartments into a self-sustaining, maladaptive ecosystem.
Deng et al. (2026) conducted a review in Idiopathic pulmonary fibrosis (IPF). Single-cell RNA sequencing and spatial transcriptomics was evaluated. Single-cell and spatial transcriptomics reveal that idiopathic pulmonary fibrosis is driven by a complex communication network among multiple cell compartments rather than a single cell type.