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Background: Pyroptosis induces neuronal death by triggering an excessive inflammatory injury. Chrysophanol possesses robust anti-inflammatory features, and it is protective against CIRI. The purpose of this research was to assess the effect of Chrysophanol post-treatment on CIRI-induced pyroptotic cell death, and to explore its underlying mechanisms. Methods: CIRI was induced in rats by CA and subsequent cardiopulmonary resuscitation, and PC12 cells were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to imitate CIRI in vitro. The survival rate, neurological outcomes, histopathological changes and cognitive functions were examined to explore the neuroprotection mediated by Chrysophanol post-conditioning. Pyroptosis-associated proteins were quantified by qRT-PCR and western blot both in vivo and in vitro model. Meanwhile, gain- and loss-of-function analyses of NLRP3 or TRAF6 were also performed to evaluate their effects on Chrysophanol-mediated anti-pyroptotic signaling pathway. Finally, the interaction between NLRP3 and TRAF6 was detected in Chrysophanol-treated PC12 cells.Results: It was found that post-CA brain injury led to a notable cerebral damage by examining histopathological changes and neurological outcomes. The existence of pyroptosis was also confirmed in in vivo and in vitro CIRI models. Moreover, we further confirmed that post-treatment with Chrysophanol, the main bioactive ingredient of Rhubarb, significantly suppressed expressions of pyroptosis-associated proteins, e.g., NLRP3, ASC, cleaved-caspase-1 and N-terminal GSDMD, and inhibited the expression level of tumor necrosis factor receptor-associated factor 6 (TRAF6). Furthermore, NLRP3 overexpression neutralized the neuroprotection of Chrysophanol post-treatment, suggesting that pyroptosis was the major neuronal death pathway modulated by Chrysophanol post-treatment in OGD/R. Additionally, the neuroprotection of Chrysophanol post-treatment was also abolished by gain-of-function analyses of TRAF6. Finally, the results demonstrated that Chrysophanol post-treatment suppressed the interaction between TRAF6 and NLRP3. Conclusions: Taken together, our findings revealed that Chrysophanol post-treatment could be protective against CIRI by inhibiting NLRP3-related pyroptosis via a TRAF6-dependent manner.