Menaquinone-4 ameliorates abdominal aortic aneurysm by suppressing ferroptosis through NRF2/GCLM axis

Abdominal aortic aneurysm (AAA) remains a lethal vascular disease lacking effective pharmacotherapies, with ferroptosis emerging as a critical pathological mechanism. This study explored the therapeutic potential of menaquinone-4 (MK4), a vitamin K2 isoform, in both porcine pancreatic elastase-induced AAA mice and Erastin-treated vascular smooth muscle cells (VSMCs). Our investigations revealed that MK4 treatment significantly attenuated AAA progression, reducing aortic dilation while maintaining vascular structural integrity. Importantly, MK4 demonstrated an excellent safety profile in all experimental models, including serum biomarker analysis. Mechanistically, MK4 exerted potent anti-ferroptotic effects in VSMCs by alleviating iron overload and reactive oxygen species (ROS) level, suppressing lipid peroxidation, and restoring glutathione homeostasis. Through RNA sequencing and chromatin immunoprecipitation assays, we identified that MK4 activates the nuclear factor erythroid-2 like 2 (NRF2)/glutamate-cysteine ligase modifier subunit (GCLM) pathway, with molecular docking confirming strong binding between MK4 and NRF2. The essential role of GCLM was validated using pharmacological inhibition, which completely abolished MK4's protective effects. Clinical relevance was further supported by pathological iron accumulation and decreased GCLM expression in human AAA specimens compared to controls. These findings establish that MK4 inhibits AAA progression through NRF2-mediated transcriptional activation of GCLM to suppress ferroptosis, positioning it as a promising and clinically translatable therapeutic candidate for this devastating vascular disease.