Organ damage proteomic signature identifies patients with MASLD at-risk of systemic complications
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Background & objectives
Metabolic steatotic liver disease (MASLD), which affects more than 30% of the world’s population, is associated with multisystemic comorbidities. We combined multidimensional OMICs approaches to explore the feasibility of using high-throughput targeted circulating proteomics to track systemic organ damage and to infer its underlying mechanisms at the molecular level.
Desing
We tested a 92-plex panel of prioritised proteins with pathophysiological relevance to organ damage in serum samples of patients with in-depth phenotyping. We included proteomics data from 60,042 people in the discovery and validation stages. The identified protein was validated across diverse study designs and cross-proteomic platforms. Deconvolution strategies were used to investigate whether the affected liver is involved in expressing biomarkers of organ damage. To assess the cell type-specific transcriptional changes of the selected target we used liver organoid data.
Results
The implicated proteins, including ADGRG1 (GPR56), are deregulated in patients with MASLD at-risk of progressive disease and significant fibrosis. ADGRG1 liver expression profile mirrors the circulation pattern. ADGRG1 levels were associated with increased risk of end-stage liver disease and a modest but clinically significant risk of death, chronic obstructive pulmonary disease, and ischaemic heart disease over 16 years of follow-up. Mechanistic insight shows that ADGRG1 shifts its transcriptional profile from low expression to upregulation in liver cells of the fibrotic niche in response to injury.
Conclusions
Our study provides a framework of potential mechanisms associated with systemic organ injury that facilitates holistic management by stratifying patients with MASLD into subclasses at-risk of extrahepatic manifestations.
