Several key insights and implications emerge from this review: (1) IFN-I signaling in pediatric SLE: robust evidence demonstrating that IFN-I signaling is significantly activated in pediatric SLE patients; (2) genetic variants and susceptibility: genetic factors, such as variants in IFN-I-related genes such as IRF5 and TYK2, have been identified as risk factors for pediatric SLE. This evidence concerns the gene IRF5 and systemic lupus erythematosus.