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Objectives Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Immune alterations often precede clinical onset, yet the molecular characteristics of this preclinical phase (pre-SLE) are not fully understood.Methods From the Taiwan Precision Medicine Initiative cohort at Taichung Veterans General Hospital, 129 individuals in the top 5% of SLE polygenic risk scores (PRS) were identified and compared with 60 healthy controls. Single-cell RNA sequencing (scRNA-seq) was performed on 57,334 PBMCs from 23 pre-SLE individuals (more than 2 SLICC criteria), 12 SLE patients, and 10 controls. Differential gene expression and immune cell composition were analyzed across disease stages.Results Among high-risk individuals, 31% met more than 2 SLICC criteria, and 2.3% fulfilled full SLE classification. scRNA-seq revealed 16 genes consistently upregulated in pre-SLE and SLE, notably IFI44L in NK cells and XAF1 in naïve CD4+ T cells, which correlated with ANA positivity, lymphopenia, and accumulation of clinical features. Pre-SLE samples exhibited early activation of cytokine signaling and mRNA poly(A) tail shortening, along with progressive TGF-beta pathway impairment via receptor downregulation. A gene signature derived from this dataset outperformed conventional interferon-stimulated gene (ISG) scores in predicting pre-SLE (AUC=0.73 vs 0.65) and SLE (AUC=0.89 vs 0.82).Abstract PT5:07 Figure 1Conclusions Single-cell profiling supports the use of SLE-PRS for identifying at-risk individuals and highlights early, targetable immune dysregulation. IFI44L (NK cells) and XAF1 (naïve CD4+ T cells) emerge as candidate early biomarkers, accompanied by TGF-beta pathway impairment. This scRNA-seq-based gene signature may facilitate early identification of individuals at risk, providing opportunities for preventive strategies before clinical disease onset.