Untargeted plasma lipidomic profiling associated with pediatric metabolic dysfunction-associated steatohepatitis (MASH)

Altered lipid metabolism is central to the pathogenesis of MASH, yet lipidomic data in pediatric populations are limited. We conducted a cross-sectional analysis using high-resolution lipidomics to identify lipid alterations associated with pediatric MASH in youth enrolled in NASH CRN studies. Clinical assessments included anthropometrics, lipid panels, liver enzymes, and markers of glucose metabolism. MASLD status was determined by liver biopsy or MRI-PDFF. Plasma untargeted lipidomics was performed using UHPLC-MS/MS. Linear models identified differentially abundant lipids. Network analysis characterized lipid-clinical associations and identified network-informed central lipids to evaluate MASH classification performance. The cohort included 102 participants with MASH (29% Zone 1, 19% Zone 3, 52% Definite) and 58 non-MASH participants (29 MASL and 29 controls). Participants were aged 7–18 years; 77% were male and 58% Hispanic, with a mean BMI Z-score of 2.01 ± 0.77. Compared with non-MASH participants, those with MASH had higher BMI Z-scores, waist circumference, liver enzymes, insulin resistance markers, and triglycerides, and lower HDL cholesterol (p < 0.05). Lipidomics analysis revealed higher levels of saturated TG species and lower levels of Cer and SM species in participants with MASH (p < 0.05). Network analysis showed greater centrality of insulin resistance markers (fasting insulin, HOMA-IR) among participants with MASH, whereas non-MASH participant networks exhibited broader lipid-clinical connectivities. Adding central lipids [TG(12:0_16:0_18:2), SM(d32:3), TG(50:5)] with a high Eigenvector Centrality Score (ECS) significantly improved MASH classification performance. Pediatric MASH was associated with plasma lipid remodeling, and network-derived central lipids improved MASH classification performance. These findings highlight the potential of lipid signatures for the noninvasive diagnosis of pediatric MASH and warrant validation in independent, longitudinal cohorts.