Crocetin antagonizes parthanatos in ischemic stroke via inhibiting NOX2 and preserving mitochondrial hexokinase-I

Parthanatos is one of the major pathways of programmed cell death in ischemic stroke characterized by DNA damage, poly (ADP-ribose) polymerases (PARP) activation, and poly (ADP-ribose) (PAR) formation. Here we demonstrate that crocetin, a natural potent antioxidant compound from Crocus sativus, antagonizes parthanatos in ischemic stroke. We reveal that mechanistically, crocetin inhibits NADPH oxidase 2 (NOX2) activation to reduce reactive oxygen species (ROS) and PAR production at the early stage of parthanatos. Meanwhile we demonstrate that PARylated hexokinase-I (HK-I) is a novel substrate of E3 ligase RNF146 and that crocetin interacts with HK-I to suppress RNF146-mediated HK-I degradation at the later stage of parthanatos, preventing mitochondrial dysfunction and DNA damage that ultimately trigger the irreversible cell death. Our study supports further development of crocetin as a potential drug candidate for preventing and/or treating ischemic stroke.

Automated summary

This study demonstrates that crocetin, a natural antioxidant compound from saffron, antagonizes parthanatos in ischemic stroke. In the early stage of parthanatos, crocetin inhibits the activation of NOX2 to reduce the production of ROS and PAR. In the later stage of parthanatos, crocetin interacts with HK-I to prevent mitochondrial dysfunction and DNA damage, ultimately preventing irreversible cell death. This study supports the further development of crocetin as a potential drug candidate for preventing and/or treating ischemic stroke.