Translational Barriers and Optimization Strategies for Remote Ischemic Conditioning to Enhance Stroke Cerebroprotection

Remote ischemic conditioning (RIC) is an endogenous strategy that mitigates cerebral injury in preclinical stroke models. However, its bench-to-bedside translation is frequently hindered by complex patient environments that induce RIC resistance and limit its neuroprotective efficacy. To bridge this translational gap, this review systematically examines the extrinsic pathophysiological and pharmacological barriers to RIC. We categorize RIC resistance into three mechanism-driven phenotypes. Impaired signal initiation (Type I) is often linked to diabetic sensorimotor polyneuropathy and the reactive oxygen species-scavenging effects of propofol. Signal transmission blockade (Type II) is associated with specific P2Y12 inhibitors and smoking-induced endothelial dysfunction. Furthermore, effector desensitization (Type III) involves target-organ unresponsiveness exacerbated by aging, chronic hyperglycemia, and postmenopausal estrogen depletion. To address these barriers, potential phenotype-specific optimization strategies are discussed. Ultimately, transitioning from generalized empirical protocols to mechanism-based precision strategies may help bypass RIC resistance in clinical settings and enhance stroke cerebroprotection.