Objective This study aims to observe the expression of IL-22 in patients with rheumatoid arthritis-associated interstitial lung disease(RA-ILD)and establish an experimental model to explore its role in pulmonary fibrosis.Methods We selected 33 patients with rheumatoid arthritis with or without interstitial lung disease,who were newly di-agnosed and treated at the Affiliated Hospital of Xuzhou Medical University from October 2021 to October 2022.Addition-ally,14 healthy subjects were chosen as controls during the same period.ELISA was used to detect the peripheral blood IL-22 levels in the three groups,and a comparison was made among them.Spearman correlation test was employed to an-alyze the correlation between IL-22 and lung HRCT scores.Logistic regression was used to analyze risk factors for RA-ILD and to draw ROC curves.Wild mice(WT)and IL-22 knock-out mice(IL-22KO)were treated with normal saline(NS)and Bleomycin(BLM).Following modeling,mice were given intraperitoneal injections of IL-22.HE and Masson staining were used to observe the histopathological changes in the lung tissues.Relevant markers were detected by RT-qPCR and Western blotting.Results The levels of IL-22 were higher in the RA-NILD group compared to the RA-ILD group and the healthy control group.There was a negative correlation between IL-22 levels and lung HRCT scores(r=-0.940,P<0.05).Logistic regression analysis suggested that a low level of IL-22 was an independent risk factor for RA-ILD.The combined diagnosis of RA-ILD with IL-22,age,smoking,APCA,and MCHC had an AUC of 0.959(95%CI:0.916-1.000),with a sensitivity of 97.0%and specificity of 87.9%.HE and Masson staining found that the collagen deposition in the lungs of BLM groups were increased compared with the NS groups,accompanied by Szapiel's scores and Ashcroft scores.The mRNA and protein expression of fibrosis-related genes(Collagen Ⅰ,Vimentin,and α-SMA)were increased in the BLM groups compared to the NS group,and the IL-22KO group showed even higher levels(P<0.05).Treatment with IL-22 resulted in a reduction in collagen deposition,mRNA,and protein expression of fibro-sis-related genes(P<0.05).Conclusion IL-22 exhibits potential as a protective effect against pulmonary fibrosis,sug-gesting it may be a potential therapeutic target and clinical predictor in the future interventions.