An integrated proteogenomic investigation of the human liver uncovers molecular drivers of steatotic liver disease
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Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing worldwide, yet effective targeted therapies remain limited. To better understand the molecular mechanisms underlying MASLD, we performed an integrated proteogenomic analysis of human liver tissue. Using mass spectrometry, we quantified 2,744 proteins in 504 liver biopsies from the Quebec Obesity Biobank and examined changes across disease stages. To investigate causality, we integrated liver proteomics with RNA sequencing and genome-wide genotyping to map thousands of protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs). These molecular data were combined with summary statistics from a meta-analysis of genome-wide association studies including 16,532 MASLD cases and 1,240,188 controls. Mendelian randomization and genetic colocalization analyses revealed that most proteins differentially expressed across MASLD stages were not causally implicated in disease risk, whereas several genetically predicted liver proteins showed evidence of causal effects. Among these, higher hepatic levels of the MTARC1 protein were causally associated with MASLD and hepatic fat accumulation. Phenome-wide analyses suggested that MTARC1 inhibition may reduce the risk of cirrhosis, hepatocellular carcinoma, and cholelithiasis while improving lipid profiles. Notably, the causal MTARC1 variant influenced liver protein levels but not gene expression. Genetic analyses also identified ERLIN1 and HSD17B13 as potential therapeutic targets. In contrast, eQTLs and pQTLs at other loci such as GCKR showed opposite effects on MASLD risk. These findings highlight the importance of integrating tissue proteomics with human genetics to distinguish biomarkers from causal drivers and to identify promising therapeutic targets for MASLD.
Created in BioRender. Gobeil, É. (2026) https://BioRender.com/ftsl0yd
In brief
Integrating liver proteomics, transcriptomics, and human genetics in 504 biopsies, this study shows that most proteins altered in MASLD are biomarkers rather than causal drivers. Genetic evidence implicates MTARC1, ERLIN1, and HSD17B13 as potential therapeutic targets and highlights the importance of protein-level regulation in liver disease.
Key points
Integrated proteomics, transcriptomics, and human genetics in 504 liver biopsies identified proteins and pathways dysregulated across MASLD stages.
Genetic analyses revealed that most differentially expressed liver proteins represent disease biomarkers rather than causal drivers of MASLD.
Proteogenomic integration identified MTARC1, ERLIN1, and HSD17B13 as potential causal proteins and therapeutic targets, and highlighted discordant effects of eQTLs and pQTLs at loci such as GCKR .
