Single‑cell and spatial transcriptomics in chronic lung disease: cellular heterogeneity and molecular mechanisms in IPF and COPD

Abstract Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have advanced the study of complex lung diseases by resolving cellular heterogeneity, tissue architecture, and intercellular communication. These technologies are particularly informative in chronic respiratory disorders, where pathological remodeling involves coordinated alterations across epithelial, stromal, immune, and endothelial compartments. Idiopathic pulmonary fibrosis (IPF), a rare fatal fibrotic disorder, and chronic obstructive pulmonary disease (COPD), a prevalent heterogeneous respiratory condition, represent distinct chronic lung diseases shaped by persistent injury, maladaptive repair, and progressive tissue remodeling. However, current understanding of their pathogenesis remains incomplete, and conventional approaches lack the resolution to define disease-associated cell states, spatially restricted niches, or compartment-specific interactions. This review synthesizes recent scRNA-seq and ST studies in IPF and COPD, emphasizing how high-resolution atlases refine established pathobiological frameworks and reveal shared and disease-specific cellular programs. We highlight epithelial dysfunction and impaired progenitor repair as shared mechanistic features of IPF and COPD, while emphasizing alveolar regenerative failure, fibroblast activation, and profibrotic niche formation as central features of IPF, and compartment-specific airway remodeling, inflammatory epithelial states, and emphysema-associated parenchymal injury as prominent features of COPD. We further discuss stromal and immune remodeling, hypoxia-associated vascular remodeling, and the translational implications of these findings for molecular stratification, target prioritization, and mechanism-informed therapeutic development, while noting limitations related to end-stage tissue sampling, platform constraints, and mouse–human correspondence. This review provides an integrated framework for understanding the cellular and spatial mechanisms underlying the pathogenesis and translational relevance of IPF and COPD.