Hspa5, also known as GRP78 or BiP, encodes a highly conserved Hsp70 family chaperone in the ER lumen. It assists in protein folding via its nucleotide-binding domain (NBD) and substrate-binding domain (SBD), and is involved in protein import into the ER, Ca2+ homeostasis regulation in the ER, and ER-associated protein degradation (ERAD). When ER is stressed, it can initiate the unfolded protein response (UPR), induce autophagy, and is associated with various diseases such as cancer, neurodegenerative and immunological diseases [2].

In the context of diseases, Hspa5 has been shown to promote the attachment and internalization of Porcine Epidemic Diarrhea Virus (PEDV) through interaction with the spike protein and the endo -/lysosomal pathway, making it a potential target for PEDV therapeutic drugs [1]. In cancers, high Hspa5 expression in breast cancer indicates a poor prognosis and is positively correlated with immune infiltration, suggesting it could be an immunotherapy target and prognostic biomarker [3]. In squamous cell carcinomas, NRF3 deficiency leads to increased Hspa5 levels, promoting cancer cell survival and migration, and Hspa5 inhibition could be a treatment strategy [4].

In conclusion, Hspa5 is a crucial chaperone in the ER with diverse functions in protein-related processes and stress responses. Its role in diseases like viral infections and cancers has been illuminated through various studies. Understanding Hspa5's functions via model-based research, especially in the context of these diseases, may provide new directions for therapeutic interventions.