Organ damage proteomic signature identifies patients with MASLD at risk of systemic complications

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease affects more than 30% of the world's population and 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 infer the underlying molecular mechanisms. APPROACH AND RESULTS: We evaluated a 92-plex panel of prioritized proteins with pathophysiological relevance to organ damage in serum samples of patients using in-depth phenotyping. We included proteomic data from 60,042 individuals in the discovery and replication stages using diverse study designs and cross-proteomic platforms. We used deconvolution strategies to investigate whether the affected liver participated in the expression of biomarkers of organ damage. To assess cell type-specific transcriptional changes in the selected target, we used liver organoid data. The implicated proteins, including ADGRG1 (GPR56), are deregulated in patients who are at risk of progressive disease and significant fibrosis. ADGRG1 was validated as a surrogate for organ damage, as it was associated with increased risk of end-stage liver disease, moderate but clinically significant risk of death, chronic obstructive pulmonary disease, and ischemic heart disease over a 16-year follow-up, regardless of the subject's metabolic dysfunction-associated steatotic liver disease status. ADGRG1 liver expression mirrors the circulation pattern. Mechanistic insights show that ADGRG1 shifts its transcriptional profile from low expression to upregulation in cells of the fibrotic and inflammatory niche in response to injury. CONCLUSIONS: Our study provides a framework for potential mechanisms associated with systemic diseases that facilitates holistic management by stratifying patients with metabolic dysfunction-associated steatotic liver disease into subclasses at risk of extrahepatic manifestations.