In conclusion, we found ten potential diagnostic biomarkers (IFI44, IFI44L, EIF2AK2, IFIT3, IFITM3, ZBP1, TRIM22, and PRIC285) for SLE by integrating bioinformatics methods, and discovered the potential of IFI44 as an optimal biomarker by five machine learning algorithms. Here, HELZ2 is linked to systemic lupus erythematosus.