Cepharanthine aggravated atherosclerosis and liver injury in Apoe −/− and Ldlr −/− mice

Background and purpose: Cepharanthine, an alkaloid purified from the earthnut Stephania Epigaea, exhibits antitumor, anti-inflammatory, and immunomodulatory effects. During the coronavirus disease 2019 (COVID-19) epidemic, cepharanthine was identified to restrain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and reduced the inflammatory response. Viral infections, which disrupt internal homeostasis, often exacerbate atherosclerosis, contributing to cardiovascular complications. Based on the antiviral and anti-inflammatory efficacy of cepharanthine and the recognition of atherosclerosis as a chronic inflammatory disease, this study aimed to evaluate whether cepharanthine could attenuate atherogenesis in two established mouse models of atherosclerosis. Methods: Atherosclerosis was induced in Apoe −/− and Ldlr −/− mice through feeding with a high-fat and high-cholesterol diet. Mice were administered 20 mg/kg cepharanthine daily for 8 weeks. Atherosclerotic lesions in the aorta and aortic sinus were evaluated using Oil Red O staining. Liver tissues were analyzed for liver injury and fibrosis using hematoxylin and eosin (H&E) and Sirius Red staining. Results: Contrary to expectations, cepharanthine aggravated atherosclerosis in both Apoe −/− and Ldlr −/− mice. Treated mice exhibited significant liver injury, characterized by hepatocyte swelling and fibrosis, with increased collagen deposition and the increased expression of Vimentin. Cepharanthine also decreased hepatic Abcg5 expression while upregulating Fabp4 expression. Elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels indicated worsened liver and heart injury in cepharanthine-treated mice. Conclusions: This study highlights potential safety concerns with cepharanthine especially for patients with hyperlipidemia, atherosclerosis, and COVID-19. These findings underscore the need for careful monitoring of its clinical use.