Ketone metabolism at the interface of atherosclerosis and brain dysfunction

Atherosclerosis and brain dysfunction converge through vascular inflammation, endothelial injury, and regional bioenergetic failure of the neurovascular unit. Ketone bodies, including acetoacetate and D-β-hydroxybutyrate, perform critical roles in metabolic signaling by serving as alternative oxidative substrates for ATP production and bioactive signaling molecules that modulate cellular pathways. In the arterial wall, ketones improve endothelial function, reduce inflammation, and shift macrophages away from proinflammatory states, as well as induce changes that are predicted to limit lesion growth and enhance plaque stability. In the brain, ketone bodies serve as alternative energy substrates under conditions of hypoperfusion or impaired glucose metabolism, while also improving synaptic resilience through mitochondrial and epigenetic mechanisms. By coupling vascular inflammation with cerebral energetics via convergent immunometabolism pathways, ketone metabolism has emerged as a versatile therapeutic target. Nonetheless, effective clinical translation will require individualized strategies that account for metabolic and genetic variability, thereby positioning personalized ketone-based interventions as a promising avenue at the critical intersection of cardiovascular disease and neurodegeneration. Thus, this review aims to summarize the evidence on metabolic alterations spanning hepatic ketogenesis to cellular utilization, highlighting the implications of these alterations for vascular function and brain function.