NMR-Based Metabolomics Reveals Metabolic Pathway Disruptions and Potential Biomarkers for Fibrosis.

Abstract

The landscape of chronic liver disease has changed significantly, with metabolic dysfunction-associated steatotic liver disease (MASLD) now emerging as the most widespread form worldwide. In Asia, particularly in India, the prevalence of MASLD is increasing, largely driven by poor dietary habits and a sedentary way of life. MASLD spans from fat deposition to inflammation and fibrosis. Fibrosis stands out as the most critical indicator of liver-related complications and overall risk of death in MASLD. Early identification of fibrosis is critical, but current tests are often invasive or unreliable. Whereas studies have explored metabolic changes in MASLD, few have focused on distinguishing early-stage fibrosis from steatosis. In this study, we used NMR-based metabolomics to analyze serum samples from n = 103 MASLD patients, divided into fibrosis (n = 44) and non-fibrosis (n = 59) groups based on standard noninvasive scoring systems. We identified seven metabolites-arginine, glycerol, aspartate, glucose, phenylalanine, histidine, and citrate-that significantly differed between the two groups and showed good diagnostic potential (AUROC > 0.70). Pathway analysis revealed disruptions in arginine and nitrogen metabolism, associated with liver scarring processes, and in energy and lipid metabolism, pointing to mitochondrial dysfunction and lipotoxic stress. Reduced aspartate levels also suggested loss of natural protection against fibrosis. This is the first study of the MASLD cohort to differentiate early-stage fibrosis from steatosis using metabolomics. Our findings highlight the potential of a simple NMR-based blood test to aid early diagnosis, guide treatment decisions, and personalize care-offering a noninvasive alternative to improve MASLD management.