Mechanisms of programmed cell death in neurodegenerative diseases and their therapeutic potential

Neurodegenerative diseases (NDDs) constitute a group of chronic and debilitating conditions affecting the central nervous system, characterized by the gradual loss of neuronal structure and function. Their pathogenesis is complex and involves multiple interrelated processes, including protein misfolding, mitochondrial dysfunction, and neuroinflammation. Increasing evidence indicates that dysregulated programmed cell death (PCD) is an important contributor to neuronal injury and disease progression. In addition to apoptosis, several non-apoptotic forms of PCD, such as necroptosis, pyroptosis, and ferroptosis, have been identified and shown to play key roles in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and other NDDs. This review summarizes the major molecular mechanisms and signaling pathways of these PCD modalities and discusses their involvement in representative neurodegenerative diseases. The interactions between PCD, neuroinflammation, and neuronal repair are also addressed. Furthermore, recent advances in therapeutic strategies targeting cell death pathways, including small-molecule inhibitors and delivery approaches, are reviewed. This work aims to provide an updated understanding of the regulatory roles of PCD in NDDs and to offer insights for the development of novel therapeutic interventions.