Cyclosporine A downregulates selenoprotein P expression via a STAT3-FoxO1 pathway in hepatocytes in vitro.

Cyclosporine A (CsA) is a worldwide applied immunosuppressant for preventing graft rejection and autoimmune diseases. However, CsA elevates oxidative stress leading to liver injuries. The present study aimed to clarify the mechanisms underlying the CsA-mediated oxidative stress. Among the redox proteins, CsA concentration-dependently downregulated Selenop encoding selenoprotein P (SeP), a major circulating antioxidant protein reducing reactive oxygen species (ROS), in hepatocytes cell lines and primary hepatocytes. The luciferase assay identified the CsA-responsive element in the SELENOP promoter containing a putative binding site for FoxO1. The CsA-mediated suppression on the SELENOP promoter was independent of NFAT, a classic target repressed by CsA. A ChIP assay showed that CsA suppressed the FoxO1 binding to the SELENOP promoter. Foxo1 knockdown significantly downregulated Selenop expression in H4IIEC3 cells. Furthermore, CsA downregulated FoxO1 by inactivating its upstream signal transducer and activator of transcription 3 (STAT3). Knockdown of Stat3 downregulated Foxo1 and Selenop expression in hepatocytes. These findings revealed a novel mechanism underlying CsA-induced oxidative stress via downregulating the STAT3-FoxO1- Selenop pathway in hepatocytes. Significance Statement Our study shows that CsA downregulates Selenop , an antioxidant protein, via suppressing the STAT3-FoxO1 pathway in hepatocytes, possibly one of the causations of CsA-induced oxidative stress in hepatocytes. The present study sheds light on the previously unrecognized CsA-redox axis.