Microplastics are emerging as a critical class of pollutants with a pervasive presence in the atmosphere, oceans, and terrestrial environments, raising global concern. However, it is unclear whether there are conserved mechanisms for the response of microplastic damage to different species. Aurelia coerulea polyps and mouse models were exposed to microplastic environments to assess their growth effects and mechanisms. The similarities and differences in the defence mechanisms of the two species after exposure to microplastics were analysed by means of phenotypic observations, transcriptome sequencing, pathological sections, oxidative stress indicators, explosions and molecular docking. Exposure to 200 mg/L of PS-MPs resulted in morphological changes, tissue damage, and oxidative stress in polyps. Exposure to 600 mg/L of PS-MPs led to increased toxicity in the mouse liver, including rupture and apoptosis of mitochondria and nuclei in hepatocytes, as well as oxidative stress. Meanwhile, we found that their antioxidant defense and DNA damage repair pathways were significantly altered. In addition, we found that the same loci existed in the foxo pathway in both species, and the enriched gene sequences were 48.33 % similar. Molecular docking showed conserved regions between polyps NLK and mouse Mapk13, indicating similar kinase activities, but overall structural and functional differences suggest species-specific. This finding provide new insights into understanding the mechanisms of toxicity of MPs to different organisms.