Yen, Ting-YuTing-YuYenCHIA-LANG HSUCHUN-YI LUNI-CHUNG LEEMING-TAI LINKuan-Ying A. HuangTan, Boon FattBoon FattTanChang, Tu-HsuanTu-HsuanChangCHUN MIN KANGWEI-SHIUNG YANGBOR-LUEN CHIANGLI-MIN HUANGHSIN-HUI YULUAN-YIN CHANG2025-11-112025-11-112025-10https://scholars.lib.ntu.edu.tw/handle/123456789/733611The 2',5'-oligoadenylate synthetase (OAS)-ribonuclease L (RNase L) system, induced by type I interferons, defends against RNA viruses. Inborn errors in this pathway may trigger inflammatory cytokines, contributing to SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C). This study examined circulating RNase L, cytokines, and chemokines in MIS-C. A prospective multicenter cohort study conducted in Taiwan from 2022 to 2023 recruited children with MIS-C, age- and gender-matched children with mild COVID-19, and healthy controls. Plasma cytokines, chemokines, and RNase L levels were measured, and clinical severity was analyzed. Among 108 children (63 boys and 45 girls), cytokine and chemokine levels positively correlated with disease severity, while RNase L levels were negatively correlated. IL-17A > 8.9 pg/mL and RNase L < 3.6 μg/mL differentiated MIS-C from mild COVID-19 (83% sensitivity, 94% specificity). CXCL9/MIG > 1129 pg/mL and RNase L < 2.8 μg/mL distinguished MIS-C patients with and without shock (79% sensitivity, 91% specificity). Findings reveal a systemic inflammatory signature in MIS-C, with pro-inflammatory, T cell activation, regulatory, and anti-inflammatory responses. Elevated IL-17A and CXCL9/MIG and decreased RNase L levels serve as sensitive biomarkers of MIS-C and disease severity.enMIS‐CRNase Lchemokineschildrencytokines[SDGs]SDG3journal article10.1002/jmv.7065041122819