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Although therapeutic strategies for acute respiratory distress syndrome (ARDS) have achieved improvements, its mortality remains high. It has been reported that microRNAs (miRs) serve as therapeutic strategies for ARDS, while specific mechanisms of miR-494 remain poorly understood. Thus, the present study aimed to assess the effects of miR-494 on acute lung injury (ALI) in rat models of sepsis-associated ARDS and its regulatory mechanism.Following establishment of sepsis-associated ARDS rat models, the ratio of wet to dry weight (W/D) in right lung tissues was detected. Moreover, the expression patterns of miR-494, NQO1 and Nrf2 were evaluated in left lung tissues of rats. The miR-494 was exogenously overexpressed in rats so as to analyze the effects of miR-494 on ALI, inflammatory response and oxidative stress. Meanwhile, the Nrf2 signaling pathway was activated in rats in order to show the regulatory mechanism of miR-494 in ALI. And the target gene of miR-494 was identified by dual-luciferase reporter assay.The findings firstly revealed upregulated miR-494, and enhanced inflammatory response, oxidative stress and ALI in rat models of sepsis-associated ARDS. Additionally, MiR-494 negatively regulated NQO1 and blocked the Nrf2 signaling pathway. Moreover, ectopic expression of miR-494 promoted inflammatory response, oxidative stress and ALI. However, the activation of Nrf2 signaling pathway reversed these effects of miR-494.Our key findings highlight the value of miR-494 inhibition as a therapeutic target for sepsis-associated ARDS, as a result of miR-494 accelerated ALI in rats with sepsis-associated ARDS through NQO1-mediated inactivation of Nrf2 signaling pathway.