by Wenhua Lv, Zhenwei Shang, Chen Sun, Yuping Zou, Siyu Wei, Haiyan Chen, Junxian Tao, Hongsheng Tian, Yu Dong, Chen Zhang, Mingming Zhang, Hongchao Lv, Yongshuai JiangEarly diagnosis of systemic lupus erythematosus (SLE) is hindered by a lack of reliable biomarkers. This study sought to identify and evaluate diagnostic plasma protein biomarkers for SLE. We analyzed plasma protein profiles, polygenic risk scores (PRS), and clinical data from 544 SLE cases and 48,036 controls in the UK Biobank. Using LASSO regression, we identified 35 high-confidence SLE-associated proteins and derived a protein risk score (ProtRS). The ProtRS model achieved exceptional diagnostic performance (AUC = 0.91), significantly outperforming models based on PRS or clinical factors alone. Notably, a cost-optimized 5-protein panel (TRIM21, SOD2, KLK3, IL15, ADIPOQ) retained high accuracy (AUC = 0.82) while reducing costs by ~87%. ProtRS also demonstrated the highest population attributable fraction (96.34%), underscoring its dominant contribution to SLE burden. This study establishes a protein-driven framework for early SLE detection, offering tiered diagnostic solutions to balance accuracy and cost. The findings underscore the translational potential of protein biomarkers in bridging theoretical research and clinical practice.