Cyclosporine A Downregulates Selenoprotein P Expression via a Signal Transducer and Activator of Transcription 3-Forkhead Box Protein O1 Pathway in Hepatocytes In Vitro.

Cyclosporine A (CsA) is an immunosuppressant applied worldwide for preventing graft rejection and autoimmune diseases. However, CsA elevates oxidative stress, which can lead 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 -encoding selenoprotein P, a major circulating antioxidant protein reducing reactive oxygen species, in hepatocytes cell lines and primary hepatocytes. The luciferase assay identified the CsA-responsive element in the promoter containing a putative binding site for forkhead box protein O (FoxO) 1. The CsA-mediated suppression on the promoter was independent of the nuclear factor of activated T-cell, a classic target repressed by CsA. A chromatin immunoprecipitation assay showed that CsA suppressed the FoxO1 binding to the promoter. knockdown significantly downregulated expression in H4IIEC3 cells. Furthermore, CsA downregulated FoxO1 by inactivating its upstream signal transducer and activator of transcription 3 (STAT3). Knockdown of downregulated and expression in hepatocytes. These findings revealed a novel mechanism underlying CsA-induced oxidative stress by downregulating the STAT3-FoxO1- pathway in hepatocytes. SIGNIFICANCE STATEMENT: This study shows that Cyclosporine A (CsA) downregulates , an antioxidant protein, by suppressing the signal transducer and activator of transcription 3-forkhead box protein O1 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.