Repges, E.; Schinhammer, S.; Al-Kassou, B.; Yousif, A.; Schott, A.; Wesendonk, D.; Bartsch, B.; Jamin, R. N.; Barthen, M.; Shamekhi, J.; Bakhtiary, F.; Baldus, S.; Kelm, M.; Oldenburg, J.; Czogalla-Nitsche, K. J.; Nickenig, G.; Zimmer, S.; Al Zaidi, M.

Background: Calcific aortic valve stenosis (AS) is the most common valvular heart disease in the aging population and lacks effective pharmacological therapy. Oxidative stress is a key feature of valvular remodeling, yet the mechanisms linking oxidative injury to calcification remain unclear. Ferroptosis, a lipid peroxidation-driven form of regulated cell death, has emerged as a key mediator of oxidative tissue injury and may contribute to cardiovascular disease. Vitamin K was recently identified as a suppressor of ferroptosis and cardiovascular calcification, but whether ferroptosis links vitamin K status to disease progression in AS remains unknown. Methods and Results: We investigated the role of lipid peroxidation and ferroptosis in AS and their modulation by vitamin K2 using a translational approach. In human stenotic aortic valves, lipid peroxidation was markedly increased and localized to calcified regions, consistent with a ferroptosis-associated microenvironment. In primary human valvular interstitial cells (VICs), pro-calcific conditions induced lipid peroxidation and a pro-ferroptotic state. Pharmacological induction of ferroptosis enhanced VIC calcification, whereas its inhibition attenuated mineralization, supporting a causal role in osteogenic remodeling. Impaired vitamin K status was associated with increased valvular lipid peroxidation in AS patients. Conversely, vitamin K2 attenuated lipid peroxidation, preserved cell viability under ferroptotic stress, and partially normalized pro-ferroptotic and inflammatory transcriptional programs in VICs. In a murine model of AS, dietary vitamin K2 supplementation attenuated disease progression, reduced transvalvular gradients, and decreased valvular inflammation and lipid peroxidation-associated pathways. Finally, in a prospective cohort of patients with aortic sclerosis to moderate AS (n = 157), circulating undercarboxylated osteocalcin, a marker of impaired vitamin K status, was independently associated with accelerated disease progression. Conclusions: Vitamin K2 counteracts ferroptosis-associated lipid peroxidation in AS and attenuates disease severity in vivo. Impaired vitamin K status is independently associated with accelerated progression in patients. These findings position vitamin K2 as a potential disease-modifying strategy and vitamin K status as a prognostic marker in AS.