〔Abstract〕 Objective To investigate the effect of paederosidic acid methyl ester(PAME) on postoperative learning and memory impairment in mice and its mechanism. Methods C57BL/6J male mice were randomly divided into Sham group, operation group, operation + PAME group(PAME group), operation + NADPH oxidase 4(Nox4) adeno-associated virus overexpression group(Nox4 overexpression group), operation + Nox4 adeno-associated virus no-laden group(AAV no-load group), and operation + PAME + Nox4 overexpression group(PN group). Exploratory laparotomy was performed. PAME(20 mg/kg) was administered by continuous gavage for 7 days after operation, and adeno-associated virus was injected into the hippocampus 28 days before operation. Morris water maze test and conditioned fear test were used to detect the learning and memory ability of mice. The expression of Nox4 protein was observed by immunofluorescence. The protein expressions of Nox4, long chain acyl CoA synthetase 4(ACSL4) and glutathione peroxidase 4(GPX4) were detected by Western blot. Reactive oxygen species(ROS) and iron content were determined by spectrophotometry. Results Compared with the Sham group, the learning and memory ability of the operation group, the Nox4 overexpression group and the AAV no-load group decreased, the protein expression of Nox4 and ACSL4 increased, the protein expression of GPX4 decreased, and the ROS and iron content increased. After PAME treatment, the postoperative learning and memory ability of mice was improved, and Nox4 and ferroptosis in hippocampal neurons were alleviated. Conclusion PAME treatment can improve the learning and memory ability of postoperative mice, which may be related to the inhibition of hippocampal Nox4-mediated ferroptosis.