Unfolded Protein Response: From cellular stress to disease pathogenesis, with insights into platelet biology

Maintaining protein homeostasis, or proteostasis, is crucial for human health and disease prevention. The endoplasmic reticulum (ER) plays a central role in protein folding and processing, making it pivotal in this process. Disruptions in proteostasis result in ER stress, triggering the unfolded protein response (UPR), which involves key targets such as PERK-eIF2α, IRE1α-XBP1, and CRT. Notably, dysregulation of the UPR has been linked to disease progression in various conditions, including neurodegenerative disorders (such as ALS, Huntington's, and Parkinson's), diabetes, atherosclerosis, lung and kidney injuries, and numerous solid tumors. However, our understanding of the involvement of UPR in heme disorders such as multiple myeloma, neutropenia, and myeloproliferative neoplasms (MPNs) remains limited, highlighting a significant gap in research. In this review, we explore the role of the UPR in various diseases, with a particular focus on heme disorders, and discuss recent findings regarding platelet-specific UPR. Further investigation into the role of UPR in these heme disorders, along with the elucidation of cell-specific mechanisms underlying its pathological roles, holds promise for gaining insights into disease mechanisms and identifying potential therapeutic strategies.