Oxeiptosis in Parkinson's disease: Unraveling the KEAP1/PGAM5/AIFM1 Axis and its role in pathophysiology and therapeutics.

Parkinson's Disease (PD) is characterized by the progressive loss of dopaminergic neurons, a process where programmed cell death (PCD) plays a central role. Oxeiptosis, a caspase-independent, reactive oxygen species (ROS)-induced PCD pathway discovered in 2018 and mediated by the Kelch-like ECH-associated protein 1 (KEAP1)/phosphoglycerate mutase 5 (PGAM5)/apoptosis-inducing factor mitochondria-associated 1 (AIFM1) axis, has emerged as a key mechanism in PD pathophysiology. This review aims to systematically elaborate on the activation mechanism of the KEAP1/PGAM5/AIFM1 signaling axis in PD. It critically analyzes how this pathway interacts with core pathological processes of PD, including mitochondrial dysfunction, neuroinflammation, and autophagic disorder, forming vicious cycles that drive disease progression. Furthermore, the review explores the significant potential and current challenges of targeting the oxeiptosis pathway as a novel neuroprotective therapeutic strategy for PD.