Endoplasmic reticulum stress in Parkinson's disease: A pivotal role in cell fate and a therapeutic target.

The endoplasmic reticulum (ER) is a central organelle that coordinates protein synthesis and processing, lipid metabolism, Ca²⁺ storage, detoxification, and cellular homeostasis. These processes are rigorously regulated, and when the ER encounters external stimuli, it triggers ER stress, a main mechanism that plays a crucial role in determining cellular fate. In addition to its role in apoptosis, further research has unveiled novel physiological functions of ER stress, encompassing its involvement in autophagic cell death, necroptosis, pyroptosis, calcium-induced cell death, and ferroptosis. Moreover, ER stress is pivotal in dopaminergic neuron degeneration, which can be triggered through multiple pathways, including chemical inducers, α-synuclein (α-syn) accumulation, and genetic mutations. Furthermore, a variety of small-molecule compounds targeting ER stress can regulate the occurrence and development of PD. Therefore, specific regulation of ER stress can eliminate harmful cellular reaction processes, providing a neuroprotective and potential therapeutic approach for PD. This review delves into the pivotal role of ER stress in various cellular processes, highlighting its significance in the context of PD.