Observational study maps sex-specific molecular architectures in MASLD using multi-omics profiling.

This is an observational primary research study involving 211 biopsy-confirmed, morbidly obese individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) undergoing bariatric surgery. The study employed paired liver-blood multi-omics profiling to characterize disease mechanisms.

The authors synthesized findings that MASLD is characterized by suppressed hepatic amino acid metabolism and extensive lipid remodeling, accompanied by inverse metabolic signatures in circulation. Sex-specific analyses revealed that disease progression in men is driven by a streamlined triacylglycerol-centric pathway mediating effects on steatosis and inflammation, whereas women exhibit distributed, multi-layered networks linking lipid, amino acid, and immune pathways. Mediation analyses identified hepatic lipid modules as key intermediates connecting gene expression to histopathology.

The study is observational, and the authors explicitly note that findings reveal associations and molecular architectures, not causation. A key limitation is that circulating biomarkers do not reflect hepatic metabolism. The authors provide a framework for sex-specific precision medicine in MASLD, but this is based on observed associations.

Practice relevance is restrained; the study offers a conceptual framework for understanding sex differences in MASLD molecular pathology, which may inform future research but does not directly guide clinical decisions.