Caspase inhibition in neurodegenerative diseases: A new therapeutic frontier

Apoptosis is defined as a form of programmed cell death that contributes to neuronal injury across a range of neurological disorders, including neurovascular and neurodegenerative diseases. It is governed by a group of cysteine proteases called caspases. Due to their significant role as signaling mediators, caspases have emerged as potential therapeutic targets. This review evaluates the current evidence on caspase involvement in neurodegeneration and explores caspase inhibition as a novel treatment approach. We performed a structured literature search from 2015 to 2025 across PubMed, Scopus, and Cochrane Central Register of Controlled Trials, supplemented by screening of ClinicalTrials.gov for interventional studies of caspase-modulating therapies in neurological disorders. We included full-text studies written in English that report neuronal outcomes and/or disease-relevant endpoints in the context of caspase inhibition or caspase-targeted modulation. Evidence was synthesized using narrative thematic analysis, stratified by disease category, caspase class, and regulated cell-death modality. Thirty-one eligible studies were included. Caspase-3 was implicated in 11 studies on Alzheimer’s disease, and caspases-1, 8, 9, and 12 were also reported in both Alzheimer’s and Parkinson’s disease. Multiple studies have reported elevated caspase activity in disease-affected brain regions and have demonstrated that pharmacological inhibition attenuated neuronal loss in preclinical models. Caspase dysregulation represents a convergent mechanism across neurodegeneration, spanning apoptosis, pyroptosis-related neuroinflammation, and pathway crosstalk. Therapeutic caspase inhibition remains promising but requires improved target selectivity, biomarker-guided trial design, and explicit evaluation of long-term risks given caspases’ homeostatic roles in neurons and immunity.