HSPA5 (also known as BiP/GRP78) is a heat shock protein family A member 5 that functions as a master regulator of endoplasmic reticulum (ER) homeostasis and stress responses. As an Hsp70 family chaperone localized in the ER lumen, HSPA5 assists protein folding via its nucleotide-binding and substrate-binding domains, facilitates ER protein translocation, regulates calcium homeostasis, and mediates ER-associated protein degradation 1. Upon ER stress, HSPA5 initiates the unfolded protein response (UPR) to manage misfolded protein accumulation and can crosstalk with apoptosis machinery 12. Beyond its canonical ER function, cell surface-translocated HSPA5 serves as a receptor for pathogenic fungi, particularly CotH proteins from Mucorales species, facilitating epithelial cell invasion during mucormycosis infection 3. In cancer contexts, HSPA5 negatively regulates ferroptosis by stabilizing glutathione peroxidase 4 (GPX4), promoting chemotherapy resistance in pancreatic adenocarcinoma 4. Additionally, HSPA5 palmitoylation and deubiquitination regulate its ER localization and activity, influencing cancer cell survival versus apoptosis decisions 56. HSPA5 is associated with multiple diseases including cancers, cardiovascular disease, neurodegenerative conditions, and immunological disorders 1, making it an emerging therapeutic target across diverse pathologies.