GRP78 in human diseases: From molecular chaperone to therapeutic target.

Glucose-regulated Protein 78 (GRP78, also known as BiP/HSPA5) is a central member of the Hsp70 family. As a key molecular chaperone in the endoplasmic reticulum (ER), it plays an important role in cell survival and biological function by maintaining protein folding homeostasis and regulating endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR). Its function is precisely regulated by various post-translational modifications (PTMs), including phosphorylation and acetylation. In addition, GRP78 can translocate to subcellular locations such as the cell membrane and nucleus, where it performs non-classical functions under stress conditions. Under pathological states, the aberrant expression and function of GRP78 are extensively involved in the onset and progression of diverse human diseases, including cancer, neurodegenerative diseases, infectious diseases, cardiovascular diseases, inflammatory diseases and metabolic diseases, and often exhibit a dual role dependent on tissue specificity and disease stage. To date, a variety of intervention strategies have been developed, such as small-molecule modulators, antibodies and genetic intervention approaches. These strategies have demonstrated promising potential in preclinical studies, yet are confronted with challenges including insufficient specificity and delayed clinical translation. This paper systematically elucidates the structure, PTMs, biological functions and disease regulatory mechanisms of GRP78, summarizes the existing intervention strategies, and discusses the unresolved issues and future research directions in this field. Future research should focus on developing highly specific regulatory tools and integrating precision medicine strategies to advance the clinical translation and application of GRP78 as a therapeutic target.