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

Authors

Jianan Xu, Xian Jin, Xuewei Li, Zhenyu Li, Bo Zhu, Lin Tian

Published in

Therapeutic advances in respiratory disease. Volume 20. Pages 17534666261491576. Epub Sep 30, 2026.

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.

PMID:
42813994
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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