IgA-Enriched Phenotype Predicts Liver-Related Events in MASLD.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex, multifactorial condition. To achieve truly personalized therapy for MASLD, it will be essential to stratify patients based on clinical and biochemical data by identifying subgroups with distinct disease mechanisms and prognostic trajectories. METHODS: This study conducted unbiased clustering analysis of 349 MASLD patients based on clinical variables. Multi-omics analyses that included spatial transcriptomics, single-cell RNA sequencing (scRNA-seq), and immunohistochemistry were subsequently applied to characterize the biological features of high-risk subgroups. RESULTS: Among the four identified MASLD subgroups, one cluster showed a higher 5-year cumulative incidence of liver-related events (LRE) (24.0%; 95% CI, 14.8%-37.4%), with excess risk persisting after adjustment for advanced fibrosis. This high-risk subgroup was characterized by an immune-driven disease phenotype with excessive IgA expression. Multivariable analysis identified elevated IgA (≥ 318 mg/dL) as an independent predictor of LRE (hazard ratio = 3.17, 95% CI 1.27-7.91; P = 0.01), a finding validated in an independent vibration-controlled transient elastography cohort (n = 287) as well as an external multicenter validation cohort (n = 272). Spatial transcriptomics and scRNA-seq analyses demonstrated portal enrichment of IgA-expressing B-lineage cells, with IGHA1-high regions showing activation of pathways related to B-cell receptor signaling, extracellular matrix remodeling, and vascular remodeling. Intestinal immunohistochemistry and circulating EndoCAb IgG levels supported a link between increased gut permeability and coordinated systemic and intrahepatic IgA-associated immune activation. CONCLUSION: A data-driven clustering strategy identified a novel MASLD subtype characterized by enhanced IgA-mediated immune activation along the gut-liver axis as a key determinant of disease progression. This IgA-based stratification improves risk assessment and enables mechanism-based therapeutic targeting in high-risk MASLD patients. IMPACT AND IMPLICATIONS: This study identified a high-risk MASLD subgroup characterized by elevated IgA levels and increased incidence of liver-related events, independent of fibrosis severity. These findings highlight the relevance of immune dysregulation, particularly IgA-associated responses, in MASLD progression.