HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is an enzyme that plays a crucial role in cholesterol biosynthesis. Research on HMGCR is important for numerous patients with atherosclerosis because inhibiting the enzyme with statins has been shown to reduce the risk of cardiovascular events such as heart attacks and strokes. Despite being generally well tolerated, statin intolerance is reported in 5-20% of patients, leading to reduced regimen adherence and statin therapy duration. In addition, HMGCR may also have a role in the development of diabetes. The goal of the Project is to discover molecular pathways linking excessive inhibition of HMGCR and hepatotoxicity, myopathy and neurological deficits. We will map the molecular effects of HMGCR deficiency in a unique mouse Hmgcr-KO model, thus advancing the understanding of mechanisms behind the statin treatment-induced tissue-specific adverse effects. We will specifically explore the role of HMGCR inliver cells and its involvement in the mechanisms of mitochondrial fatty acid metabolism. All this will help to evaluate the hypothesis of HMGCR as a crucial enzyme for maintaining cellular energy metabolism balance and to drive discovery of innovative approaches to prevent and treat cardiometabolic diseases.