BACKGROUND Romidepsin (FK228) or depsipeptide, is a selective inhibitor of histone deacetylase 1 (HDAC1) and HDAC2. This study aimed to investigate the effects and molecular mechanisms of romidepsin (FK228) in a mouse model of acute kidney injury (AKI) induced by lipopolysaccharide (LPS). MATERIAL AND METHODS The mouse model of AKI was developed by intraperitoneal injection of LPS. The mice were also treated intraperitoneally with romidepsin (FK228) six hours following injection of LPS. Markers of renal injury were measured, including blood urea nitrogen (BUN), serum creatinine (SCR), and serum cystatin C (Cys C) were measured. Histology and transmission electron microscopy were performed to evaluate tissue injury further. Levels of HDACs were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) assays were used to investigate the regulation of CYP2E1 expression. RESULTS Treatment with romidepsin (FK228) significantly reduced the levels of BUN, SCR, and Cys C induced by LPS. Histology of the mouse kidneys showed that treatment with romidepsin (FK228) reduced the degree of renal injury. CYP2E1 significantly reduced following treatment with romidepsin (FK228) in the mouse model of AKI. Also, acetylation of H3 was upregulated following treatment with romidepsin (FK228), and binding of hepatocyte nuclear factor-1 alpha (HNF-1a) on the CYP2E1 promoter was significantly increased. CONCLUSIONS In a mouse model of LPS-induced AKI, treatment with romidepsin (FK228) downregulated the expression of CYP2E1 by inhibiting the binding if HNF-1a with the CYP2E1 promoter to reduce renal injury.