Hepatic transcriptional effects of simvastatin and the possible impact on COVID-19

Background and Aims: Recent reports show an association between statins therapy and reduction in 28-day all-cause mortality among Coronavirus disease 2019 (COVID-19) patients. This association is poorly understood mechanistically. Hence, we investigated whether simvastatin regulates hepatic expression of genes involved in humoral and innate immune responses, and in the activation of classical pathways of the complement system. Methods: Forty patients eligible for cholecystectomy were randomized to 28-day treatments with simvastatin (80 mg/day), ezetimibe (10 mg/day), combination therapy (simvastatin + ezetimibe), or placebo before surgery. Liver biopsies were collected during the surgical intervention. Pooled RNA libraries were sequenced and RNA-seq reads were mapped to the human genome. Results: A total of 260 genes were differentially expressed by the different treatment regimens. Of particular interest in the statin monotherapy is the downregulation of chemokine ligand 13 (CXCL13), a novel marker of systemic immune activation during acute RNA viral infection. The gene ontology and pathway analyses of the differentially expressed genes further proved the unique immunomodulatory effects of statin mono- and combination therapy. Conclusions: Our pivotal study identifies immunomodulatory effects of a statin that contributes to the understanding of the recently proposed protective role of statin use in the novel coronavirus (SARS-CoV-2) infection and COVID-19 morbidity and mortality disease outcomes.