Ischemic stroke remains one of the leading causes of death and long-term disability worldwide, yet the therapeutic window for intervention is measured in hours and most neuroprotective drugs have failed in clinical translation. A growing body of molecular research is now focusing on why — and protein–protein interactions (PPIs) may hold a critical part of the answer. Rather than targeting single receptors or enzymes in isolation, PPI-focused approaches aim at the scaffolding logic of cellular signaling itself, potentially explaining why so many single-target drugs have disappointed in stroke trials.
This review from Acta Pharmacologica Sinica maps the PPI-mediated signaling architecture driving ischemic neuronal death. The authors examine how discrete molecular complexes — including those governing excitotoxicity, neuroinflammation, oxidative stress cascades, and blood-brain barrier breakdown — are organized through protein–protein binding interfaces. Key pathways dissected include NMDA receptor-associated postsynaptic density complexes, NF-κB signaling scaffolds, and apoptotic regulatory interactions such as Bcl-2 family heterodimers. The review also catalogs emerging small-molecule and peptide-based PPI disruptors under preclinical and early clinical investigation as candidate neuroprotectants.
From a research landscape perspective, PPI-targeted drug discovery has matured significantly over the past decade, buoyed by advances in cryo-electron microscopy and AI-assisted structure prediction that make previously "undruggable" interfaces tractable. In the stroke field specifically, this approach addresses a fundamental limitation: ischemia triggers a cascade of overlapping, redundant death signals, meaning blockade of any single node is often insufficient. Disrupting the molecular scaffolds that coordinate multiple pathways simultaneously could offer broader neuroprotection. That said, this is a review article, not a clinical trial, so its primary value lies in synthesizing preclinical evidence and identifying high-priority therapeutic targets rather than demonstrating clinical efficacy. Translation from rodent ischemia models to human stroke has historically been poor, and that barrier remains. Still, the mechanistic framework presented here is directionally important for drug developers and clinicians following the neuroprotection field.