Idiopathic Pulmonary Fibrosis: Cellular Heterogeneity, Mechanisms, and Therapeutic Implications

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and irreversible alveolar destruction. Despite advances in antifibrotic therapies, the underlying pathogenic mechanisms remain incompletely understood. Recent multiomic studies have revealed that IPF arises from aberrant communication among epithelial, mesenchymal, immune, and vascular cells within the fibrotic microenvironment, rather than from isolated cellular dysfunction. However, the dynamic intercellular networks and spatiotemporal regulation driving disease progression remain poorly defined. This review integrates recent single-cell RNA sequencing and spatial transcriptomic discoveries to delineate key pathogenic cell populations—including aberrant basaloids and IPF-related alveolar type 2 cells (IR_AT2), CTHRC1⁺ and meflin⁺ fibroblasts, and SPP1^hi macrophages—and their signaling crosstalk through pathways such as transforming growth factor β(TGF-β), Hippo, and Hedgehog. We further discuss how ECM feedback loops and immune-metabolic remodeling reinforce fibrogenesis and explore emerging therapeutic targets derived from these mechanisms. By synthesizing multidimensional data into a cellular and molecular framework, this review advances the understanding of IPF pathogenesis and provides a conceptual foundation for biomarker-guided precision therapies.

Keywords

epithelial cells / fibroblasts / immune cells / IPF / scRNA-seq / spatial transcriptomics

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