The multi-target protective effects of quercetin in cerebrovascular diseases: a dietary strategy for endothelial repair and neuroprotection

Cerebrovascular diseases, including ischemic stroke and vascular cognitive impairment, represent a significant global health challenge due to the paucity of effective treatment options. Quercetin, a dietary flavonol, has emerged as a promising multi-target neuroprotective compound. This review elucidates the core mechanisms by which quercetin achieves vascular repair and neuroprotection in cerebrovascular diseases through synergistic regulation of multiple signaling pathways and explores strategies to bridge the gap between dietary intake and clinical application. At the vascular level, quercetin enhances antioxidant defense by activating the nuclear factor E2-related factor 2/heme oxygenase-1 axis, inhibits the Toll-like receptor 4/nuclear factor-κB pathway and NOD-like receptor protein 3 inflammasome, and maintains blood-brain barrier integrity by inhibiting matrix metalloproteinase-9 and upregulating tight junction proteins via the Wnt/<i>β</i>-catenin signaling pathway. At the neural level, quercetin inhibits apoptosis through the brain-derived neurotrophic factor-PI3K/Akt pathway, promotes M1-to-M2 microglial polarization to control neuroinflammation, and enhances synaptic plasticity. Additionally, quercetin exerts beneficial effects on mitochondrial protection and calcium homeostasis regulation. However, quercetin currently faces significant barriers to bioavailability, including low oral bioavailability and limited ability to cross the blood-brain barrier. Emerging nanotechnology-based delivery systems, including liposomes, exosomes, and reactive oxygen species-responsive nanoparticles, can enhance brain targeting and bioavailability. Future research should prioritize promoting dietary patterns rich in flavonoid compounds while developing advanced formulations validated through rigorous clinical trials. This approach will help clarify effective dosages, safety profiles, and clinical endpoint benefits across different stages of cerebrovascular disease. In summary, quercetin represents a promising candidate for cerebrovascular disease intervention; however, technological innovations are urgently needed to overcome bioavailability limitations and generate conclusive clinical evidence.