Through a comprehensive screening and rigorous validation using five machine learning algorithms, six OS-related key genes highly correlated with SLE (EIF2AK2, AKR1C3, ABCB1, NPC1, IFIH1, SCO2) were ultimately identified and further confirmed in additional datasets for their predictive performance and associations with immune cell subsets. Here, EIF2AK2 is linked to systemic lupus erythematosus.