Abstract: ob＜x＞jective: To investigate the ex＜x＞pression of neuregulin 4 (Nrg-4) and its receptor ErbB4 in gingival crevicular fluid (GCF) of patients with periodontitis and their effects on periodontal tissue inflammation and alveolar bone loss in experimental periodontitis rat model. Methods: A total of 20 healthy participants (H group, n=20) and 60 patients with periodontitis were recruited and divided into periodontitis group (G group, n=20), stage II grade B periodontitis group (P1 group, n=20) and stage III grade B periodontitis group (P2 group, n=20). The GCF of all participants was collected, and the ex＜x＞pression levels of ErbB4, Nrg4, IL-6 and IL10 in GCF were detected by using ELISA assay, the ratio of IL-6/IL10 was calculated and Pearson’s correlation analysis was performed. In vivo experimental periodontitis rat model was constructed. A total of 15 rats were randomly divided into sham operation group (S group), model group (M group) and Nrg4 recombinant protein treatment group (T group), 5 rats for each group. Micro-CT imaging analysis, followed by the H&E staining and histopathological analysis were performed to analyze the condition of the above three groups of rats ’ maxillary periodontitis sites. GCF of the three groups of rats was also collected and measured the ratio of IL-6/IL10 to evaluate the inflammation levels. Results: Compared with group H, the ex＜x＞pression of ErbB4 in GCF of patients in the different stages of periodontitis, group G ( p<0.05), group P1 (p<0.01) and group P2 (p<0.01) was significantly increased, and the ex＜x＞pression of ErbB4 in GCF of the group P2 was higher than that of the group G (p<0.05). While, compared with group H, the ex＜x＞pression of Nrg4 in GCF of patients in the different stages of periodontitis, group G (p<0.01), group P1 (p<0.01) and group P2 (p<0.01) was significantly decreased. At the same time, the ex＜x＞pression of ErbB4 in the GCF of periodontitis group G (r2=0.4184, p =0.0021), P1 (r2=0.7314, p<0.0001) and P2 (r2=0.2867, p=0.0150) patients was positively correlated with the ratio of IL-6/IL10 within the group, respectively. The ex＜x＞pression of Nrg4 in the GCF of periodontitis group G (r2=0.4135，p=0.0022), P1 (r2=0.3589，p=0.0052) and P2 (r2=0.3650，p=0.0048) patients was negatively correlated with the ratio of IL-6/IL10 within the group, respectively. In vivo animal model study by using micro-CT imaging analysis showed that the use of Nrg4 recombinant protein to treat periodontitis rat model showed good curative effects. Compared with M group, in the T group, the distance between the cement-enamel junction and the alveolar bone crest (CEJ-ABC) was significantly reduced ( p<0.01), bone mineral density (BMD) (p<0.01) and bone/tissue volum (BV/TV) ( p<0.01) increased significantly; the ratio of IL-6/IL10 decreased significantly (p<0.01), while there is no significant difference of the above 4 parameters between the T group and the S group. Conclusion: The ex＜x＞pression levels of ErbB4 and Nrg4 in GCF can be used as potential markers of inflammatory levels in patients with periodontitis. The Nrg4 recombinant protein has shown a good curative effects in the treatment of periodontitis in vivo.