Protein-protein interaction-mediated signaling networks in ischemic stroke: from molecular mechanisms to therapeutic strategies.

The pathological progression of ischemic stroke is driven by a dynamic signaling network mediated by protein-protein interactions (PPI) that involves excitotoxicity, oxidative stress, neuroinflammation, and regulated cell death (RCD), ultimately leading to neurological dysfunctions. Instead of functioning independently, these PPI-driven pathways engage in extensive cross-talk, creating cycles that exacerbate the injury over both space and time. Therapeutic strategies designed to disrupt key nodal PPIs, comprising small molecule inhibitors, peptide mimetics, and chimeras targeting proteolysis (PROTACs), have shown promise. However, clinical translation faces several major challenges, including the structural complexity of PPIs, the efficiency of blood-brain barrier (BBB) penetration, and the adaptive, multifactorial nature of the ischemic cascade. Emerging approaches are now shifting from single-target inhibition to network-level intervention, utilizing artificial intelligence (AI)-guided drug development, multi-target PPI regulators, and context-responsive delivery systems to achieve spatiotemporal precision. Through the integration of multidisciplinary technologies and mechanism-driven innovative designs, PPI-targeted strategies provide a promising approach to reprogramming the ischemic brain for repair, moving beyond traditional neuroprotection to dynamic network medicine.