Navigating Cellular Stress: Endoplasmic Reticulum Stress and the Unfolded Protein Response in the Molecular...

Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality worldwide, characterized by a complex and not yet fully understood pathophysiology. This paper examines the increasingly important roles of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the pathogenesis of PE. The ER, vital for protein folding, calcium homeostasis, and lipid synthesis, responds to cellular stressors via the UPR pathway. In PE, pathological placental hypoxia compromises mitochondrial and ER function, leading to persistent ER stress marked by upregulation of stress markers like GRP78 and heightened activation of UPR signaling arms-IRE1, ATF6, and PERK. This initiates a harmful feed-forward cycle, increasing endothelial dysfunction, inflammation, and oxidative stress. Current therapeutic strategies targeting these pathways are mainly in preclinical stages, as antioxidant therapies have shown varied clinical outcomes. Despite challenges in understanding disease heterogeneity and ensuring safety during pregnancy, new treatments focusing on precise molecular modulation of ER stress responses show promise. This review synthesizes current knowledge on ER stress in PE and highlights potential therapeutic targets, aiming to enhance maternal and fetal outcomes and transform clinical management of this condition.