Cerebral injury after cardiac arrest (CA) is a frequent cause of death and diminished quality of life among patients who have successfully undergone cardiopulmonary resuscitation (CPR); however, treatment options remain limited. Artesunate (Art), primarily an antimalarial compound with well-documented anti-inflammatory properties, has also demonstrated efficacy in mitigating ischemia-reperfusion injury. Herein, we explored the role of Art in mitigating cerebral injury after CA and its potential mechanisms. In vivo models of CA/CPR were established in mice via potassium chloride injection and in swine via electrical stimulation. For the in vitro experiments, a cell model was created by subjecting Neuro-2a cells to hypoxia/reoxygenation (H/R). Knockdown of NEDD4 was achieved through infection with adeno-associated virus or small interfering RNA. After treatment with Art, a series of methods were employed to evaluate neurological function, cerebral injury severity, cell pyroptosis, and neuroinflammatory responses. Art markedly improved neurological function, reduced neuronal death, and attenuated the inflammatory response following CA, and these therapeutic effects were linked to the inhibition of neuronal pyroptosis. Further investigations revealed that Art upregulated NEDD4 expression, which enhanced its binding to caspase-11, inhibited the activation of gasdermin D (GSDMD), and thereby suppressed caspase-11/GSDMD-mediated pyroptosis. Notably, knockdown of NEDD4 increased the ubiquitination of caspase-11 and reversed the neuroprotective effect of Art under both H/R and CA/CPR conditions. Overall, Art effectively ameliorated cerebral injury following CA, with the associated mechanism potentially involving the inhibition of caspase-11/GSDMD-mediated pyroptosis via the upregulation of NEDD4.
