BackgroundThe role of histone methyltransferase SETDB1 in renal ischemia–reperfusion (I/R) injury has not been explored yet. This study aims to investigate the potential mechanism of SETDB1 in regulating renal I/R injury and its impact on mitochondrial damage and oxidative stress.MethodsThe in vivo model of renal I/R in mice and the in vitro model of hypoxia/reoxygenation (H/R) in human renal tubular epithelial cells (HK-2) were constructed to detect the expression of SETDB1. Next, the specific inhibitor (R,R)-59 and knockdown viruses were used to inhibit SETDB1 and verify its effects on mitochondrial damage and oxidative stress. Chromatin immunoprecipitation (ChIP) and coimmunoprecipitation (CoIP) were implemented to explore the in-depth mechanism of SETDB1 regulating renal I/R injury.ResultsThe study found that SETDB1 had a regulatory role in mitochondrial damage and oxidative stress during renal I/R injury. Notably, SESN2 was identified as a target of SETDB1, and its expression was under the influence of SETDB1. Besides, SESN2 mediated the regulation of SETDB1 on renal I/R injury. Through deeper mechanistic studies, we uncovered that SETDB1 collaborates with heterochromatin HP1β, facilitating the labeling of H3K9me3 on the SESN2 promoter and impeding SESN2 expression.ConclusionsThe SETDB1/HP1β-SESN2 axis emerges as a potential therapeutic strategy for mitigating renal I/R injury.