Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits marked heterogeneity and sex differences, yet the molecular mechanisms underlying disease progression remain incompletely understood. Here, we present the largest integrative multi-omics study to date combining matched liver tissue and blood profiling in 211 biopsy-confirmed, morbidly obese individuals with MASLD undergoing bariatric surgery. We integrate hepatic transcriptomics, metabolomics, and lipidomics with serum metabolomics to resolve compartment-specific and sex-dependent molecular networks. Across sexes, MASLD is characterized by suppressed hepatic amino acid metabolism and extensive lipid remodeling, accompanied by inverse metabolic signatures in circulation, consistent with systemic spillover. Strikingly, disease progression in men is driven by a streamlined triacylglycerol-centric pathway that mediates transcriptional effects on steatosis and inflammation, whereas women exhibit distributed, multi-layered networks linking lipid, amino acid, and immune pathways. Mediation analyses identify hepatic lipid modules as key intermediates connecting gene expression to histopathology. These findings reveal sex-specific molecular architectures of MASLD, demonstrate that circulating biomarkers do not reflect hepatic metabolism, and provide a framework for sex-specific precision medicine.

In the last 5 years S.R. received research grants from Novonordisk and AstraZeneca for basic science research on steatotic liver disease, and has been consulting for AstraZeneca, GSK, Celgene Corporation, Ribocure AB, Madrigal, Ultragenyx, Amgen, Sanofi, Wave Life Sciences, Lipigon, Novartis, Profluent, Aina, Echosense and Chiesi; declares equity from Heptabio; and is inventor on a Patent with title 'Method for treating fatty liver disease', on PSD3, US application number 17,480266 filed on 21st September 2021. Other co-authors have no conflict of interest to declare.

M.O. and T.H. were supported by the "Investigation of endocrine-disrupting chemicals as contributors to progression of metabolic dysfunction-associated steatotic liver disease" (EDC-MASLD) consortium funded by the Horizon Europe Program of the European Union under Grant Agreement 101136259. Views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. S.R. was supported by the Region Stockholm (ALF project grant, FoUI-1021801), the Swedish Cancerfonden (22 2270 Pj), the Swedish Research Council (Vetenskapsradet (VR), 2023-02079), the Swedish state under the Agreement between the Swedish government and the county councils (the ALF agreement, ALFGBG-965360), the Swedish Heart Lung Foundation (20220334), the Novonordisk Distinguished Investigator Grant – Endocrinology and Metabolism (NNF23OC0082114), the Novonordisk Project grants in Endocrinology and Metabolism (NNF24OC0091535, and a Novo Nordisk donation to the Karolinska Institutet in connection with the professor appointment.

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The study has been approved by the Local Research Ethics Committee at Campus Bio-Medico University Hospital (approval no. 16/20), and by the Swedish Ethics Review Authority (Dnr 2025-08073-01), and it was conducted in accordance with the principles of the Declaration of Helsinki. All participants gave written informed consent to the study.

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