Endoplasmic reticulum stress and maladaptive repair in fibrotic interstitial lung diseases: A human-evidence-based narrative review.

Abstract

Fibrotic interstitial lung diseases (ILDs) are characterized by progressive extracellular-matrix accumulation but arise from biologically diverse injuries. This narrative review examines endoplasmic reticulum (ER) stress as a context-dependent regulator of maladaptive repair, prioritizing evidence from human genetics, tissue, single-cell and spatial studies, patient-derived systems, biomarkers, and clinical trials. In selected familial surfactant disorders, pathogenic variants provide direct evidence that impaired proteostasis can cause fibrotic lung disease. In sporadic idiopathic pulmonary fibrosis (IPF), epithelial unfolded protein response (UPR) signatures and KRT8/KRT17-enriched transitional states are associated with arrested alveolar regeneration, but do not establish a single causal pathway. IRE1α, PERK-eIF2α, and ATF6 can support adaptive proteostasis during acute stress yet may contribute to inflammatory signaling, epithelial injury, or differentiation arrest when activation is persistent. Human spatial studies place stressed epithelium within SPP1-positive macrophage, activated-fibroblast, and endothelial niches, although ER-stress activity outside epithelium remains less certain. Evidence is strongest in IPF and familial surfactant disorders; extension to progressive pulmonary fibrosis, connective-tissue-disease-associated ILD, or fibrotic hypersensitivity pneumonitis remains inferential. Current antifibrotic and PDE4B-directed therapies slow functional decline but do not demonstrate correction of epithelial proteostasis. Direct ER, UPR, or integrated-stress-response strategies have not established human efficacy in fibrotic ILD. Future studies should define disease- and cell-specific repair states, measure target engagement longitudinally, and test interventions during potentially reversible windows of repair arrest. Why lung scarring can continue after injury. Why was this review done? Some lung diseases cause too much scar tissue to form. This makes the lungs stiff and can make breathing difficult. We reviewed studies involving people to understand why normal healing sometimes stops and scarring continues. What did the review find? Cells lining the tiny air sacs of the lungs make proteins and fats that keep the lungs working normally. When these cells are injured, they switch on a stress response and try to repair the damage. This response may help after a short injury. However, if it continues for too long, some cells may become trapped between an injured state and a fully healed state. Studies of human lung tissue show that these cells are often found near immune cells and cells that make scar tissue. The evidence is strongest for idiopathic pulmonary fibrosis and some rare inherited lung diseases. Evidence for other types of lung scarring is less certain. What does this mean? Current medicines can slow the loss of lung function, but no treatment has yet been shown to restore normal healing by directly changing this cell response. Future studies should identify which patients still have lung cells that can recover and test whether treatment helps those cells return to normal function.