Pulmonary Fibroblast Heterogeneity and Functional Remodeling in Idiopathic Pulmonary Fibrosis: State Persistence and Reversibility
Year: 2026
Type: article
Abstract: Pulmonary fibrosis is a common pathological endpoint of several interstitial lung diseases. Idiopathic pulmonary fibrosis (IPF), in particular, has an unknown cause, produces progressive scarring of the lung parenchyma, and carries a poor prognosis. Single-cell and spatial omics studies have shown that lung fibroblasts comprise multiple populations with distinct anatomical locations and functional states. However, how these states are established, interconverted, and maintained in the injured microenvironment remains incompletely understood and has not been directly validated. This review uses IPF as the primary clinical context and draws complementary mechanistic evidence from other fibrotic lung diseases and animal models. It examines fibroblast origins and state heterogeneity; signaling networks involving transforming growth factor-β (TGF-β), Wnt, and Yes-associated protein (YAP); interactions among epithelial cells, immune cells, and fibroblasts; and epigenetic and metabolic remodeling. On this basis, we propose a two-layer stability model of epigenetic maintenance and signaling feedback as a working framework for understanding the persistence of profibrotic states. We also discuss how treatment might move from nonselective inhibition toward restricting pathological states, eliminating pathogenic subpopulations, and preserving reparative function. The causal sequence proposed by this model, the necessity of its components, and the thresholds for state reversal remain unresolved and require testing through lineage tracing, assessment of phenotypic stability after stimulus withdrawal, and sequential combination interventions.
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7225610119