The review discusses the decision-making mechanism between autophagy and apoptosis in response to endoplasmic reticulum (ER) stress. ER stress triggers the unfolded protein response (UPR), which can either promote autophagy to maintain cellular homeostasis or lead to apoptosis if the stress is excessive. The UPR involves three main pathways: IRE1, PERK, and ATF6, which regulate autophagy and apoptosis through complex feedback loops. These loops, both within and between UPR branches, fine-tune the response to ER stress, ensuring the cell chooses between survival and death based on the stress level. Under low ER stress, autophagy is induced, while apoptosis remains inactive. However, with increased stress, the balance shifts, and apoptosis becomes dominant. The study highlights that autophagy often precedes apoptosis, even at high stress levels, as it provides a survival mechanism. The UPR's dynamic regulation, including positive and negative feedback loops, allows the cell to adapt to stress. For example, the PERK pathway activates autophagy through the ATF4-GADD34 loop, while the IRE1 pathway promotes apoptosis via the JNK pathway. The review also emphasizes the role of cross-talk between UPR branches and other signaling pathways, such as NF-κB, in modulating the stress response. Systems biology analysis reveals that the UPR's regulatory network can exhibit bistability, allowing the cell to choose between autophagy and apoptosis based on the stress level. This dynamic behavior is crucial for maintaining cellular homeostasis and preventing fatal outcomes. The study underscores the importance of understanding these mechanisms for developing therapeutic strategies in diseases associated with ER stress, such as diabetes, neurodegenerative disorders, and cancer.The review discusses the decision-making mechanism between autophagy and apoptosis in response to endoplasmic reticulum (ER) stress. ER stress triggers the unfolded protein response (UPR), which can either promote autophagy to maintain cellular homeostasis or lead to apoptosis if the stress is excessive. The UPR involves three main pathways: IRE1, PERK, and ATF6, which regulate autophagy and apoptosis through complex feedback loops. These loops, both within and between UPR branches, fine-tune the response to ER stress, ensuring the cell chooses between survival and death based on the stress level. Under low ER stress, autophagy is induced, while apoptosis remains inactive. However, with increased stress, the balance shifts, and apoptosis becomes dominant. The study highlights that autophagy often precedes apoptosis, even at high stress levels, as it provides a survival mechanism. The UPR's dynamic regulation, including positive and negative feedback loops, allows the cell to adapt to stress. For example, the PERK pathway activates autophagy through the ATF4-GADD34 loop, while the IRE1 pathway promotes apoptosis via the JNK pathway. The review also emphasizes the role of cross-talk between UPR branches and other signaling pathways, such as NF-κB, in modulating the stress response. Systems biology analysis reveals that the UPR's regulatory network can exhibit bistability, allowing the cell to choose between autophagy and apoptosis based on the stress level. This dynamic behavior is crucial for maintaining cellular homeostasis and preventing fatal outcomes. The study underscores the importance of understanding these mechanisms for developing therapeutic strategies in diseases associated with ER stress, such as diabetes, neurodegenerative disorders, and cancer.