The role of remote ischemic conditioning in ischemic stroke: neuroprotective mechanisms and future directions

Despite advances in vessel recanalization, ischemic stroke remains a leading cause of mortality, highlighting the need for comprehensive neuroprotective strategies such as remote ischemic conditioning (RIC). This review evaluates the multitargeted mechanisms of RIC, its progress in clinical translation, and the key factors determining its efficacy. In preclinical models, RIC exerts neuroprotection by modulating neuroinflammation, preserving the blood-brain barrier, and promoting angiogenesis and remyelination. Notably, it suppresses multiple programmed cell death pathways, including pyroptosis, apoptosis, ferroptosis, and disulfidptosis. However, analyses of recent high-quality clinical trials (e.g., SERIC-EVT, RESIST, and RICAMIS) reveal heterogeneous efficacy, indicating that clinical success is highly dependent on the specific execution protocol and successful cerebral reperfusion. Furthermore, critical patient-specific variables such as circadian rhythms, baseline systemic inflammation, and levels of both lipoprotein(a) and mean corpuscular hemoglobin (MCH) significantly influence therapeutic outcomes. Ultimately, while RIC is a highly translatable therapeutic strategy, its successful clinical application relies on the standardization of treatment protocols, the use of precision medicine to identify optimal responders, and its integration with existing therapies to maximize long-term stroke recovery.