Previous studies have suggested a correlation between uric acid (UA) and lung lesion in some diseases. However, it remains unknown whether UA contributes to the lung injury in rheumatoid arthritis (RA). Our study aimed to investigate the clinical value of the UA level in the severity of rheumatoid arthritis–associated interstitial lung disease (RA-ILD). We measured UA in serum and bronchoalveolar lavage fluid (BALF), and UA levels of subjects were compared. As for the role of UA on ILD, we incubated A549 cells with UA and the expression of EMT markers was measured by immunofluorescence staining. The concentrations and messenger RNA expression of IL-1, IL-6, and transforming growth factor-β (TGF-β) were measured by ELISA and RT-PCR, respectively. We observed that serum UA levels in RA were significantly higher than those in controls. And, higher UA was measured in both serum and BALF of patients with RA-ILD, particularly those with interstitial pneumonia (UIP) pattern. Additionally, the correlation of the serum and BALF UA levels with serum KL-6, a biomarker of ILDs, in RA was significant (r = 0.44, p < 0.01; r = 0.43, p < 0.01). And, the negative correlations of UA, in both serum and BALF, with forced vital capacity (r =  −0.61, p < 0.01; r =  −0.34, p < 0.01) and diffusing capacity for carbon monoxide (r =  −0.43, p < 0.01; r =  −0.30, p < 0.01) were measured in patients. In the ROC curve analysis, the AUC value of UA for RA-ILD was 0.744 (95% CI: 0.69–0.80; p < 0.01), and the AUC of serum UA for predicting UIP pattern of patients with RA-ILD was 0.845 (95% CI: 0.78–0.91; p < 0.01), which showed the significance of the UA in clinical settings. Also, the in vitro experiment showed that UA induced epithelial-to-mesenchymal transition (EMT) and production of IL-1, IL-6, and TGF-β in A549 cells. Therefore, the elevated UA levels may be a diagnostic marker in RA-ILD, particularly RA-UIP.

STIP1-homologous U-Box containing protein 1 (STUB1) is involved in the development of immune pathologies and the regulation of T cell. However, the potential role of STUB1 in the pathogenesis of rheumatoid arthritis (RA), especially in the regulation of T cells, remains elusive. Here we show that STUB1 promotes the imbalance of Th17/Treg cells through non-degradative ubiquitination of AHR. Using Western blot and flow cytometry analysis, we observe that the level of STUB1 was increased in RA patients compared with healthy controls. In particular, the expression of STUB1 protein was different in Th17 cells and Treg cells of RA patients. We also demonstrated that STUB1 facilitates Th17/Treg imbalance by up- or down-regulating the expression of STUB1. In a subsequent series of in vitro experiments, we revealed that STUB1 promoted the imbalance of Th17 and Treg cells through non-degradative ubiquitination of AHR. Both knockdown of the AHR expression by siRNA and assays of CYP1A1 enzymatic activity by Ethoxyresorufin-O-Deethylase (EROD) supported this conclusion. Furthermore, we explored the ubiquitination sites of AHR responsible for STUB1-mediated ubiquitination and revealed that STUB1 promotes ubiquitination of AHR via K63 chains. Together, STUB1 may induce the imbalance of Th17/Treg cells via ubiquitination of AHR and serve as a potential therapeutic target for RA.