Pharmacological mechanisms of natural products with antidepressant effects: A focus on the programmed cell death regulation

Depression is a prevalent mental disorder characterized by persistent disinterest and a depressed mood, with severe cases potentially leading to suicide. In recent years, the incidence of depression has steadily increased, making it the second-largest global health burden. The pathogenesis of depression involves a series of complex pathological mechanisms, although the key underlying causes remain unclear. Programmed cell death (PCD), including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, involves highly organized gene expression processes that may influence the occurrence and development of depression by regulating cellular fate. Furthermore, numerous studies have shown that natural products can modulate PCDs through various signaling pathways, presenting significant potential for managing depression. Natural products offer benefits such as cost-effectiveness, fewer side effects, and other advantages, making them viable supplements or alternatives to traditional antidepressant drugs. To explore this potential, we reviewed studies demonstrating the antidepressant effects of natural products through multi-target modulation of PCDs. In addition, we discussed the toxicity and clinical applications of these natural products. This study highlights that diverse core biological pathways and targets are involved in determining the fate of depression-associated brain cells, including the PI3K/Akt signaling pathway, caspase-8, GSDMD, and others. In conclusion, the multi-target mechanisms of PCD regulation by natural products may provide a promising foundation for the future development of novel antidepressant medications.