Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy

Endoplasmic reticulum (ER) stress is a key cellular mechanism that is important in the development of many diseases, including cancer. Since the discovery of the unfolded protein response (UPR), research has greatly improved our understanding of how ER stress affects cellular functions, especially protein folding and adaptation to stress. The UPR consists of three main branches: IRE1, ATF6, and PERK, each of which is crucial for regulating stress responses, protein homeostasis, and apoptosis. These pathways normally help cells handle stress effectively; however, excessive or prolonged activation can lead to cell death and disease progression. In cancer, ER stress not only shapes the tumor environment but also supports immune evasion, making treatment more challenging. Moreover, ER stress is linked to a wide range of other diseases, including cardiovascular diseases, neurodegenerative disorders, metabolic issues, and autoimmune diseases. ER stress can cause inflammation, protein buildup, and disrupted immune responses in these cases. Targeting the pathways involved in ER stress is a promising therapeutic approach with the potential to reduce disease severity and improve treatment outcomes by restoring cellular balance. The current review systematically integrates current findings on the signaling pathways and regulatory mechanisms of ER stress, examines its role in a wide range of diseases, and explores potential therapeutic strategies aimed at modulating this response. By focusing on the complex relationship between ER stress and different diseases, this investigation aims to guide future research and clinical efforts targeting ER stress-related pathways.