Effects of low-dose monacolin K on the circulating proteome in individuals with suboptimal cholesterolaemia: A randomised clinical trial

Red yeast rice (RYR) is a traditional Chinese product obtained by fermenting rice with the yeast Monascus purpureus and contains monacolin K, which is chemically identical to lovastatin, a drug with cholesterol-lowering activity. The European Food Safety Authority (EFSA) has evaluated the safety and efficacy of RYR supplements for managing cholesterol levels. In 2018, EFSA published a scientific opinion on the use of monacolin K from RYR in food supplements, concluding that monacolins from RYR may raise significant safety concerns at a use level of 10 mg/ day. Following that, the European Commission declared in 2022 that RYR products must contain less than 3 mg of monacolins for daily consumption. The aim of this work was to perform a comprehensive profiling of plasma markers of muscle and liver dysfunction by extensive untargeted plasma proteomics in healthy volunteers with suboptimal cholesterolaemia who were randomly assigned to receive a dietary supplement containing RYR (total monacolin <3 mg) or placebo for one month. No changes in classical markers of liver (AST, ALT) or muscle (CPK) function were detected in the plasma samples of patients treated with the supplement compared to placebo. Interestingly, the analysis of circulating proteins marking an early acute response in the liver, such as serum amyloid A4, orosomucoid 2, haptoglobin-related protein, prothrombin, α-1-antitrypsin, α-2-HS-glycoprotein, serum amyloid P (APCS), orosomucoid 1, c-reactive protein (CRP) and α-2-macroglobulin confirmed an overlapping profile in the two groups. Similarly, the analysis of ryanodine receptor 1, titin, dystrophin and myosin 7 again showed a similar profile in the two groups. These data indicate that a low dose of monacolin K (<3 mg/day) in subjects with suboptimal cholesterolaemia does not increase levels of markers of liver and skeletal muscle function in plasma, excluding a deleterious effect of monacolin K on these tissues.