Abstract: Objective To explore the expression changes of serum sulfatase 1 (Sulf1) and metabolomics in heart failure patients and analyze their diagnostic value. Methods The 2024 follow-up cohort from "Huai'an Chronic Disease Prevention and Control Study" was selected. Serum samples were collected from 19 heart failure patients and 20 healthy controls. Sulf1 levels in both groups were detected by RT-PCR, while amino acid levels were measured by ultra-high-performance liquid chromatography coupled with tandem quadrupole mass spectrometry (UHPLC-MS/MS). Spearman correlation analysis was performed to assess the correlation between Sulf1 and amino acids. Binary logistic regression analysis was conducted to identify risk factors for heart failure. The diagnostic performance of Sulf1 and amino acids for heart failure was evaluated using receiver operating characteristic (ROC) curves. Results The Sulf1 levels in the heart failure group were significantly higher than those in the healthy control group (P<0.05). Correlation analysis showed that tryptophan and threonine were correlated with Sulf1 in the heart failure group (r=-0.365, P=0.022; r=-0.383, P=0.016). ROC analysis indicated that the areas under the curve (AUC) for tryptophan,threonine, and Sulf1 in diagnosing heart failure were 0.850, 0.766, and 0.711, respectively. The combined AUC was 0.858. Conclusions Threonine, tryptophan, and Sulf1 are associated with heart failure. The combination of these three markers demonstrates superior diagnostic performance compared to any single marker alone in cardiovascular patients and may contribute to the diagnosis of heart failure.