摘要Acute kidney injury(AKI),triggered by various stimuli including ischemia-reperfusion,nephrotoxic insult,and sepsis,is characterized by an abrupt deterioration in kidney function.Ubiquitination is a post-translational modification of proteins that plays a critical role in the pathogenesis and progression of AKI.In this study,we aimed to investigate the role and underlying mechanism of the deubiquitinating enzyme Josephin Domain-containing protein 2(JOSD2)in AKI.We found that deficiency of JOSD2 exacerbated renal tubular injury and inflammation in AKI mice induced by cisplatin or ischemia-reperfusion injury.Conversely,the specific overexpression of JOSD2 in renal tubular epithelial cells effectively prevented renal tubular injury and inflammation induced in AKI mice.Mechanistically,we identified Sirtuin 7(SIRT7)as a potential substrate of JOSD2 through mass spectrometry combined with co-immunoprecipitation analysis.JOSD2 removes the K63-linked ubiquitination of SIRT7 via its active site C24 and promotes P62-mediated autophagic degradation of SIRT7,which subsequently prevents the phosphorylation and nuclear translocation of P65 and reduces inflammatory responses in renal tubular epithelial cells.Our study reveals the role of the JOSD2-SIRT7 axis in regulating AKI-induced renal inflammation and highlights the potential of JOSD2 as a promising therapeutic target for AKI.