Deciphering the pulmonary fibrosis niche: A single-cell transcriptomic perspective on cellular crosstalk and microenvironment remodeling.

Abstract

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.