ABSTRACT Enhancer of zeste homolog 2 (EZH2), a well‐known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a critical role in various kidney diseases. Previous studies have demonstrated that EZH2 contributes to ischemia–reperfusion (I/R)‐induced acute kidney injury (AKI). However, the specific role and regulation of EZH2 in renal I/R injury remain incompletely understood. This study provides a comprehensive analysis of EZH2's role and underlying mechanisms in renal ischemia–reperfusion injury. Inhibition of EZH2 reduces apoptosis and ameliorates I/R‐induced AKI in both in vitro and in vivo models. Global gene expression analysis by RNA‐seq and ChIP‐seq reveals a marked upregulation of Spalt‐Like Transcription Factor 1 (SALL1) and its involvement in the Wnt signaling pathway in EZH2‐knockdown HK‐2 cells. Mechanistically, Cancer Susceptibility Candidate 15 (CASC15) recruits EZH2 to the SALL1 promoter, where EZH2 catalyzes H3K27me3 modification. ChIP analysis further confirms the enrichment of EZH2 at the SALL1 promoter. Additionally, silencing of SALL1 exacerbates hypoxia‐induced apoptosis in HK‐2 cells through inactivation of β‐catenin. In conclusion, CASC15 recruits EZH2 to the SALL1 promoter, where EZH2 mediates H3K27me3 modification to suppress SALL1, thereby regulating the Wnt/β‐catenin signaling pathway in renal I/R injury. The CASC15/EZH2/SALL1 axis represents a promising therapeutic target for the treatment of AKI.
Zhang et al. (Sat,) studied this question.