Degradation of histone deacetylase 6 alleviates ROS-mediated apoptosis in renal ischemia-reperfusion injury.

Renal ischemia reperfusion injury (RIRI) is an inevitable complication during renal surgery. Histone deacetylase 6 (HDAC6), a key member of the histone deacetylase family, is associated with multiple pathologies, including renal diseases. However, whether HDAC6 could become a potential therapeutic target for clinical application of RIRI remained to be proven. Here, we found that HDAC6 expression was abnormally enhanced by the transcription factor OSR2 in RIRI. Moreover, we were the first to validate that a selective HDAC6 degrader, proteolysis-targeting chimeras (PROTAC) NP8, could significantly improve RIRI. Further in vivo and in vitro mechanism studies have found that the reduction of HDAC6 alleviated RIRI by inhibiting ROS mediated apoptosis. Remarkably, a renal protective protein, Klotho, has been proven to be a target of HDAC6, and the degradation of HDAC6 restored KL expression, thereby ameliorating ROS mediated apoptosis. Overall, our results illustrated that the degradation of HDAC6 restrained ROS mediated apoptosis by restoring Klotho expression during RIRI. PROTAC-NP8 might be a potential therapeutic strategy for clinical prevention of RIRI.