Endoplasmic reticulum stress and the unfolded protein response in lung diseases: molecular pathways and therapeutic interventions

Endoplasmic reticulum stress (ERS) occurs when the protein-folding capacity of the endoplasmic reticulum (ER) is overwhelmed, triggering the unfolded protein response (UPR) to restore homeostasis. However, severe or persistent ERS can shift the UPR toward pro-inflammatory, apoptotic, and fibrotic signaling, thereby exacerbating tissue injury. The pathogenesis and progression of lung diseases, which involve highly heterogeneous cell populations, are significantly influenced by these mechanisms. Indeed, ERS and UPR activation are now recognized as central players in the pathophysiology of numerous lung diseases. This review examines the impact of dysregulated ERS/UPR signaling across different lung diseases, with a particular focus on its cell-type-specific effects and disease-specific implications. Furthermore, we discuss emerging therapeutic strategies designed to modulate these pathways. A comprehensive understanding of the cell-type-specific outcomes of ERS/UPR is therefore crucial for developing targeted interventions to mitigate or reverse lung disease progression. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.