Programmed cell death pathways in Parkinson's disease: Spotlight on ferroptosis and pyroptosis

Parkinson's disease (PD) characterized by the selective loss of dopaminergic neurons in the brain resulting in motor and cognitive deficits. While apoptosis has long been considered a primary mechanism of neuronal death in PD, emerging evidence highlights the significant roles of non-apoptotic programmed cell death pathways, particularly ferroptosis and pyroptosis-in driving PD progression. Ferroptosis is form of cell death that is dependent on iron and driven by lipid peroxidation, appears to be associated with PD. On the other hand, Pyroptosis, a caspase-1-dependent inflammatory cell death pathway mediated by activation of inflammasome and release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18. Both pathways contribute to the neurodegeneration in PD through distinct yet interconnected pathways. Therefore, this review highlights molecular mechanisms underlying ferroptosis and pyroptosis in PD and recent advances in pharmacological strategies targeting these pathways.