In this study, we demonstrated for the first time that 4-OI improves renal function and alleviates injury of tubular cells in S-AKI via activating the Nrf2 pathway and blunting the STAT3 overactivation, indicating that 4-OI might be a promising therapeutic candidate for the treatment of sepsis-induced AKI in the future. Here, NFE2L2 is linked to acute kidney injury.