Menaquinone-7 in Atherosclerosis: Integrated Modulation of Endothelial Dysfunction, Oxidative Stress, and Vascular Inflammation

Atherosclerosis is a chronic inflammatory arterial disease and the primary underlying cause of cardiovascular morbidity and mortality worldwide. Its development and progression are driven by a mechanistically interconnected triad of endothelial dysfunction, oxidative stress, and vascular inflammation. Current pharmacotherapy, primarily focused on low-density lipoprotein cholesterol (LDL-C) reduction through statin-based and adjunctive therapies, does not fully address the residual inflammatory and calcific components of atherosclerotic risk. Menaquinone-7 (MK-7), a long-chain isoform of vitamin K2 with superior bioavailability and extrahepatic tissue distribution, has emerged as a multi-target modulator of atherogenic processes. Its classical function is to serve as a cofactor for the gamma-carboxylation of vitamin K-dependent proteins (VKDPs), principally matrix Gla protein (MGP), the primary endogenous inhibitor of vascular calcification. Beyond this established pathway, a growing body of experimental evidence indicates that MK-7 may modulate endothelial nitric oxide (NO) production through carboxylation-dependent activation of Growth Arrest-Specific Protein 6 (Gas6) and suppress lipid peroxidation and ferroptosis via Ferroptosis Suppressor Protein 1 (FSP1)-mediated reduction of vitamin K hydroquinone (VKH2). In addition, it may attenuate nuclear factor kappa-B (NF-κB)-driven inflammatory gene transcription in vascular cells. Previous reviews mainly focused on how vitamin K2 influences vascular calcification and cardiovascular outcomes. However, emerging mechanistic evidence linking MK-7 to endothelial dysfunction, oxidative stress, ferroptosis, and vascular inflammation has not been comprehensively integrated. This review summarizes the current knowledge of in vitro, animal, observational, and randomized controlled trial evidence for MK-7 in the context of atherosclerosis. It particularly emphasises mechanistic pathways, the strength of evidence, and translational limitations, highlighting the lack of direct human vascular evidence in several areas.