Acute kidney injury (AKI) is a common multifactorial adverse effect of surgery, circulatory obstruction, sepsis or drug/ toxin exposure that often results in morbidity and mortality. Sphingolipid metabolism is a critical regulator of cell survival and pathologic inflammation processes involved in AKI. Opaganib (also known as ABC294640) is a first-in-class experimental drug targeting sphingolipid metabolism that reduces the production and activity of inflammatory cytokines and, therefore, may be effective to prevent and treat AKI. Methods: Murine models of AKI were used to assess the in vivo efficacy of opaganib including ischemia-reperfusion (IR) injury induced by either transient bilateral occlusion of renal blood flow (a moderate model) or nephrectomy followed immediately by occlusion of the contralateral kidney (a severe model) and lipopolysaccharide (LPS)-induced sepsis. Biochemical and histologic assays were used to quantify the effects of oral opaganib treatment on renal damage in these models. Results: Opaganib suppressed the elevations of creatinine and blood urea nitrogen (BUN), as well as granulocyte infiltration into the kidneys, of mice that experienced moderate IR from transient bilateral ligation. Opaganib also markedly decreased these parameters and completely prevented mortality in the severe renal IR model. Additionally, opaganib blunted the elevations of BUN, creatinine and inflammatory cytokines following exposure to LPS. Conclusion:The data support the hypotheses that sphingolipid metabolism is a key mediator of renal inflammatory damage following IR injury and sepsis, and that this can be suppressed by opaganib. Because opaganib has already undergone clinical testing in other diseases , the present studies support conducting clinical trials with this drug with surgical or septic patients at risk for AKI.