Non-Resolving Repair in Idiopathic Pulmonary Fibrosis: From Failed Cellular Transitions to Architectural Lock-In.

Repair programs are pervasive in idiopathic pulmonary fibrosis (IPF), yet they fail to reach completion. While single-cell and spatial omics have identified cellular states associated with injury-repair programs, a central paradox remains: why do these programs persist without reconstituting functional lung architecture? This review integrates evidence from multiscale omics, spatial analyses, and translational studies to propose a lesion-centered "non-resolving repair" framework that explains IPF progression. We argue that disease progression is driven by the persistence of cellular repair programs after the pathways required for maturation, state exit, and microenvironmental reset have become compromised. These compartment-specific failures converge within spatially organized lesion units, where aberrant cellular activity and matrix distortion reinforce one another, embedding failed repair within tissue architecture. This perspective shifts the focus from cataloging disease-associated cell states toward evaluating failed biological transitions and regional resolution capacity. Clinically, it reframes antifibrotic therapy around overcoming spatial barriers to repair and highlights the need for translational endpoints that distinguish marker suppression from structural stabilization and functional tissue reconstruction. Delineating which lesional niches retain resolution capacity will be essential for identifying where repair-oriented interventions may still re-engage organized tissue repair in IPF.