Blood Metabolites as Biomarkers and Metabolism Mechanism Studies of Hemorrhagic Fever With Renal Syndrome

Hemorrhagic Fever with Renal Syndrome (HFRS) is a potentially life‐threatening hantavirus zoonosis endemic to East Asia, especially China, featuring fever, hemorrhage, and acute renal injury. This study aimed to identify serum metabolic biomarkers for HFRS staging and explore impaired metabolic pathways. We performed untargeted serum metabolomic profiling via ultra‐performance liquid chromatography tandem mass spectrometry (UPLC‐MS/MS) on samples from acute‐phase, convalescent HFRS patients, and healthy controls. Data from untargeted metabolomics showed that 168 metabolites were significantly altered in HFRS patients. Among these, 14 metabolites could distinguish the pairwise group comparisons (patient/NC, AP/CP, AP/NC, and CP/NC), with univariate AUCs ranging from 0.7556 to 1.000; a LASSO‐based combined model yielded leave‐one‐out cross‐validated (LOOCV) AUCs of 1.000, 0.993, and 0.840 for AP/NC, CP/NC, and AP/CP, respectively, indicating their potential to distinguish disease stages. Pathway analysis revealed significant perturbations in arginine biosynthesis, ascorbate and aldarate metabolism, and taurine and hypotaurine metabolism, indicating the importance in the metabolic dysfunction of HFRS. Metabolites within the arginine biosynthesis pathway were markedly altered and effectively differentiated acute‐phase HFRS from healthy controls, suggesting their role in predicting acute disease status. Distinct serum metabolite abundance shifts can stratify HFRS stages. The 14 metabolites and their combined panels discriminated disease stages with univariate AUCs of 0.756–1.000 and leave‐one‐out cross‐validated AUCs of 0.840–1.000, supporting serum metabolites as candidate biomarkers for distinguishing HFRS stages and providing a basis for targeted metabolomics studies of HFRS.