Relationship of unfolded protein response key protein BiP/GRP78 with diseases and research progress on its inhibitors

[Background] Immunoglobulin heavy-chain binding protein(BiP), also named as glucose regulatory protein 78(GRP78), is a chaperone protein that is predominantly expressed in the lumen of the endoplasmic reticulum(ER).As the master regulatory chaperone of the unfolded protein response(UPR), BiP coordinates three UPR signaling pathways(IRE1α, ATF6, and PERK)during ER stress, preserving ER proteostasis and cellular viability.Beyond UPR, the complex molecular interactions of BiP with key signaling pathways such as Akt, Wnt and PERK have been explored.In response to cellular stress, BiP can escape from the ER and move to the plasma membrane where it functions as a receptor for many ligands and behaves as an autoantigen that contributes to cancer and other human diseases.Furthermore, this review highlights BiP's role in modulating mechanisms of cancer, including UPR regulation, cell proliferation, migration and invasion, emphasizing its significance in cancer resistance.Apart from cancer, BiP also plays important roles in the development of other diseases, such as neurodegenerative diseases, autoimmunity and viral infections.BiP-mediated support of cancer cell, immune dysregulation, and atherosclerosis has established its potential as a therapeutic target.[Progress] Recent advancements in elucidating BiP's functional and disease-modulating pathways have spurred the development of several BiP-targeted inhibitors.Targeting BiP is regarded as a potentially promising therapeutic strategy for cancer.This review focuses on the mechanisms by which BiP contributes to disease pathogenesis through its regulation of immune responses, cellular apoptosis, and critical signaling pathways and systematically examines recent progress in the development of BiP-targeted inhibitors.[Perspective] This review systematically analyzes the structural characteristics, inhibitory mechanisms, and relative merits and demerits of these inhibitors to inspire further research.Additionally, the therapeutic potential of targeting BiP-associated chaperone networks, post-translational modifications, and inhibitors with immunogenic cell death(ICD)-inducing activity are also discussed as novel strategies for drug discovery, with the aim of providing new opportunities for BiP-targeted antitumor therapy.Overall, this review summarizes the physiological functions of BiP in disease development and recent advances in the development of BiP inhibitors.