Background: Hyperhomocysteinemia often results from vitamin deficiency and/or an unhealthy lifestyle. Because the condition is a risk factor for developing cerebrovascular disease or atherosclerosis, approaches that decrease plasma homocysteine level are needed to alleviate this public health issue. Unfortunately, as the standard treatment of supplementation with B vitamins has shown limited benefit, novel therapies must be explored. We have recently focus on two novel approaches, the first being a preventive approach through diet by supplementation with polyphenols, and the other a reinforcement of homocysteine metabolism by targeting the principal organ of homocysteine metabolism, the liver. Chronic supplementation of polyphenols decreased plasma homocysteine and LOX-1 level in hyperhomocysteinemic mice. Plasma homocysteine level also significantly decreased after hepatocyte-specific DYRK1A gene transfer in hyperhomocysteinemic mice, DYK1A being an enzyme implicated in different aspects of homocysteine metabolism. Aim: We aimed to extend our previous findings by analyzing the effect of hepatocyte-specific Dyrk1a gene transfer on plasma LOX-1 level in hyperhomocysteinemic mice. Materials and methods: Plasma LOX-1 level and some signalling pathways in aorta were assessed by ELISA and RPPA. Results: Hepatocyte-specific DYRK1A gene transfer restored plasma LOX-1 level and Pi3K/Akt/mT or pathway in aorta of hyperhomocysteinemic mice. Discussion: Hepatocyte-specific DYRK1A gene transfer makes it possible to normalize plasma homocysteine level and its associated endothelial dysfunction by restoring LOX-1 level in hyperhomocysteinemic mice as previously found with polyphenols supplementation.