Altered Tryptophan-Kynurenine Pathway and Low-Grade Inflammation in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Insights from LC-MS/MS-Based Metabolite Profiling.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystem disorder characterized by hepatic lipid accumulation, low-grade inflammation, and metabolic dysregulation. Although the kynurenine pathway has been implicated in the pathogenesis of metabolic and inflammatory diseases, its contribution to MASLD remains unclear. This study aimed to evaluate tryptophan (TRP) metabolism and its relationship with inflammatory biomarkers and lipid parameters across different grades of steatosis. A total of 88 adults (62 MASLD, 26 healthy controls; aged 20-69 years) were enrolled in this study. Serum concentrations of inflammatory markers (CRP, IL-6, and TNF-α) were determined using immunoassay-based methods, and TRP metabolites (TRP, KYN, KYNA, 3-HK, 3-HAA, QA, PIC) were quantified using validated LC-MS/MS. Steatosis grades (0-3) were assessed via ultrasonography. Statistical analyses included the Mann-Whitney U test, the Kruskal-Wallis test, and the Spearman correlation test. MASLD subjects showed significantly higher BMI, triglycerides, AST, ALT, GGT, CRP, TNF-α, and KYNA levels compared with controls (all P < .05), while HDL-C levels were lower (P = .014). Across steatosis grades, BMI, TG, and CRP increased progressively (P < .001), and IL-6 showed a positive correlation with steatosis severity (r = .280, P < .05). KYNA levels were elevated in early steatosis (Grade 1, P = .008) and inversely correlated with TC and LDL-C (r = -.393 and r = -.384, respectively). The elevation of KYNA may reflect an early compensatory mechanism imitigating hepatic and metabolic stress. Integrating inflammatory and kynurenine pathway biomarkers could improve disease stratification and therapeutic targeting in MASLD.