Hyperhomocysteinemia-Driven Ischemic Stroke: Unraveling Molecular Mechanisms and Therapeutic Horizons

Homocysteine is a toxic intermediate in the metabolism of methionine, and impaired homocysteine metabolism can lead to hyperhomocysteinemia, whose clinical relevance to ischemic stroke has been confirmed by many studies and is considered an independent risk factor for ischemic stroke. This article reviews and analyzes studies related to ischemic stroke due to hyperhomocysteinemia. Firstly, the mechanism of hyperhomocysteinemia was examined, and it was clarified that hyperhomocysteinemia is the result of mutations in the genes of key enzymes involved in homocysteine metabolism or nutritional disorders of cofactors involved in homocysteine metabolism. Secondly, we reviewed that hyperhomocysteinemia may lead to a series of pathological processes such as vascular injury, thrombosis, and vasoconstriction through the mechanisms of inflammation and oxidative stress, neurotoxicity, and epigenetic dysregulation, which ultimately lead to the development of ischemic stroke. The article also provides a review of research on the prevention and treatment of ischemic stroke associated with hyperhomocysteinemia, specifically describing three large clinical vitamin supplementation trials, which, despite the heterogeneity of findings, provide partial evidence for prevention. This review will provide some insights and thoughts for studying the biological mechanisms of hyperhomocysteinemia-associated ischemic stroke and exploring novel therapies for its prevention and treatment.