GRP78 in viral pneumonia: dual regulatory mechanisms and translational prospects

Glucose-regulated protein 78 (GRP78), a core molecular chaperone governing the endoplasmic reticulum (ER) stress response, exerts dual regulatory effects during the pathogenesis of viral pneumonia. Beyond serving as a critical cofactor that promotes viral invasion and replication, GRP78 functions as an indispensable protective chaperone that preserves pulmonary cellular homeostasis and attenuates lung injury. This review characterizes two distinct subcellular localizations of GRP78 in viral pneumonia, namely ER-resident GRP78 and cell surface GRP78 (csGRP78), and systematically summarizes its dual regulatory mechanisms. Specifically, csGRP78 mediates viral adhesion and internalization, whereas ER-GRP78 promotes viral replication and aggravates pulmonary inflammation by modulating ER stress and the unfolded protein response. Meanwhile, GRP78 alleviates pulmonary tissue damage via suppressing lung cell apoptosis and restraining excessive ERS activation. Moreover, this review provides a comprehensive overview of advances in GRP78-targeted therapeutic strategies. The covered therapeutic modalities include small-molecule inhibitors, biological macromolecular drugs, indirect regulatory compounds, and natural products. This review also elaborates their specific molecular targets, core mechanisms, and preclinical findings. Additionally, the current research trends, existing limitations, and future perspectives of GRP78-related investigations are critically discussed. This review aims to clarify the central regulatory role of GRP78 in viral pneumonia, providing theoretical basis and innovative research directions for the precision targeted therapy of viral pneumonia.