Unfolded protein response in bronchopulmonary dysplasia: mechanisms, pathways, and therapeutic implications

Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in preterm infants, characterized by impaired alveolarization and abnormal vascular development. Growing evidence indicates that endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are closely involved in the pathogenesis of BPD. Under hyperoxic conditions, excessive reactive oxygen species promote protein misfolding and accumulation within the endoplasmic reticulum, leading to activation of the three major UPR branches—IRE1, PERK, and ATF6. Dysregulation of these pathways contributes to lung injury and disrupted development through multiple stress-responsive cellular processes. This review summarizes current understanding of the molecular mechanisms by which UPR signaling participates in hyperoxia-induced lung injury in BPD and discusses therapeutic strategies with potential relevance to UPR modulation, including caffeine, vitamin A, and tauroursodeoxycholic acid (TUDCA), among others, based on available clinical and preclinical evidence. Although some agents have demonstrated clinical benefits in reducing BPD-related outcomes, whether these effects are mediated directly through UPR modulation remains uncertain. In contrast, several UPR-targeting compounds have shown promise in experimental models but lack clinical validation regarding safety and efficacy. Further studies are needed to clarify the cell-type-specific roles of UPR signaling in the developing lung, to better define the transition from adaptive to maladaptive UPR activation, and to support translational efforts that integrate mechanistic insights with clinical investigation. Such advances may help bridge the gap between molecular understanding and therapeutic development for BPD.