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Acute kidney injury (AKI) is a frequent and serious complication of sepsis, which results in a rapid decline of kidney function. Currently, there are no curative therapies for AKI. Theacrine is a purine alkaloid and exerts significant role in regulating inflammation, oxidative stress, and mood elevation. The study aims to evaluate the biological role and potential mechanism of theacrine in septic AKI. The murine and cellular models of septic AKI were established in lipopolysaccharide (LPS)-treated C57BL/6 mice and HK-2 cells, respectively. The effect of theacrine on alleviating septic AKI was assessed after pretreatment with theacrine in vivo and in vitro. We found that theacrine treatment significantly alleviated LPS-induced kidney injury, as evidenced by decreased levels of kidney injury markers (blood urea nitrogen and creatinine), inflammatory factors (IL-1β and IL-18), and cell apoptosis in vivo and in vitro. Mechanistically, theacrine markedly repressed the activation of NOD-like receptor (NLR) pyrin domain-containing protein 3 (NLRP3)inflammasome. As expected, MCC950 (a specific inhibitor of NLRP3) treatment also decreased LPS-induced production of IL-18 and IL-1β and cell apoptosis in HK-2 cells. More important, Nigericin sodiumsalt (a NLRP3 agonist) damaged the effect of theacrine on repressing kidney injury markers (blood urea nitrogen and creatinine), pro-inflammatory cytokines (IL-18 and IL-1β), and cell apoptosis. Taken together, these results demonstrate that theacrine alleviates septic AKI, at least in part by repressing the activation of NLRP3 inflammasome.