Chrysophanol inhibits ischemia/reperfusion-induced neuronal pyroptosis by regulating NRF2/ARE/GSDMD signaling pathway

Chrysophanol (CHR) has been shown to afford significant neuroprotection on ischemic stroke (IS). This study aimed to investigate the effects of CHR on cerebral ischemia/reperfusion (I/R).

MCAO/R was used to establish mouse IS model. Histological analysis was performed using Nissl staining. Neuronal loss was detected using TUNEL staining. OGD/R was used to establish in vitro cerebral I/R injury model. Gene expression was detected using RT-qPCR and Western blot. Cytokine release was detected using ELISA. Cellular functions were detected using CCK-8 assay, LDH assay, flow cytometry, and TUNEL staining. GSDMD transcription was detected using luciferase and ChIP assays.

CHR alleviated OGD/R induced neuronal damage, as well as inhibited oxidative stress, inflammatory response, and neuronal pyroptosis in vivo and in vitro. CHR promoted the activation of NRF2/ARE signaling. NRF2 inhibited the transcription of GSDMD, resulting in its downregulation. However, inhibition of NRF2 signaling contributed to neuronal damage and pyroptosis.

CHR protects against cerebral I/R injury-induced neuronal loss by regulating NRF2/ARE/GSDMD signaling pathway. Therefore, CHR may be a promising strategy for cerebral I/R injury.