Background: The triglyceride-glucose (TyG) index has a significant relationship with the incidence of coronary artery disease and has been proposed to bridge insulin resistance (IR) and acute coronary syndrome (ACS). Our study explores the relationship between the metabolomic profile and the TyG index of patients with ACS. Methods: The study involved 30 participants divided into 4 groups based on the quartiles of the TyG index: Q1 TyG group (n=9), Q2 TyG group (n=6), Q3 TyG group (n=7), and Q4 TyG group (n=8). We analyzed the participants’ cardiometabolic characteristics and metabolomic profiles. Results: The four groups differed in frequency of mitral insufficiency (p=0.030) and glycemia (p=0.013). Independently from age, dyslipidemia, and diabetes, the TyG index showed a negative correlation with the frequency of family history of ACS (p=0.036), HDL-cholesterol (p=0.041), and eGFR (p=0.016). In addition, the TyG index was positively associated with the presence of mitral (p<.001) and tricuspid (p=0.008) insufficiency, and with the level of total cholesterol (p=0.044), triglycerides (p<.001), creatinine (p=0.008), 2-hydroxy-3-methylvalerate (p=0.032), 2-methoxy acetaminophen glucuronide (p=0.016), 2-methoxy acetaminophen sulfate (p=0.011), 5alpha-androstan-3beta,17alpha-diol disulfate (p=0.040), alpha-hydroxyisovalerate (p=0.027), azelate nonanedioate (p=0.001), glycolithocholate sulfate (p=0.019), X–11838 (p=0.010), X–11843 (p=0.023), X–11850 (p=0.007). In the regression analysis, the model considering azelate nonanedioate was highly significant (p<0.001) and explained 52% (adjusted R2) of the variance in the TyG index. Azelate nonanedioate levels in the Q4 TyG group were higher than the Q1 TyG group with a trend towards significance (p=0.056). Conclusions: The TyG index is linearly correlated with specific metabolites, particularly azelate nonanedioate, in subjects with ACS regardless of diabetes. Azelate nonanedioate inhibits the Trx/TrxR system, which is involved in adipose tissue physiology, carbohydrate metabolism, IR, and atherogenesis. Azelate nonanedioate might mediate the adverse effects of IR on myocardial tissue in the development of ACS.