Integrated serum proteomic and liver genomic analyses identify molecular signatures associated with metabolic dysfunction-associated steatotic liver disease: a multi-cohort study

BACKGROUND: Circulating proteomics acts as an intermediate phenotype linking genetic susceptibility to MASLD. However, current evidence rarely establishes a direct concordance between serum protein levels and hepatic gene expression. We aimed to perform a multi-cohort joint analysis of serum proteomics and transcriptomics to characterize essential molecular features for MASLD. METHODS: For the serum proteomic analysis of simple steatosis (MASL), we conducted a cross-sectional investigation in an MRI-based cohort (N/cases: 1048/428) and further examined the prospective association between protein features and MASL incidence (N/cases: 2945/1947) ascertained by ultrasonography over a median 9.8-year follow-up in the Guangzhou Nutrition and Health Study (GNHS) cohort. In parallel, we characterized fibrosis and MASH-related transcriptional features using liver transcriptomics from the MASH cohort (N = 94) and validated these gene signatures for MASH in liver transcriptomes from the independent Japanese and German populations (N = 98 and 59). RESULTS: The serum proteomic analysis identified the C3, C9, F9, VTN, AFM, APOD, APOF, and SHBG proteins were significantly associated with MASL risk (P < 0.05). Liver transcriptomic analysis revealed a coordinated downregulation of C9, C4BPB, C1RL, APOF, and ITIH4 in the high NAS group, implicating dysregulated complement activation as a critical mechanism driving disease progression. Furthermore, SHBG, A2M, GSN, C7, LUM, IGHG3, and IGFALS were associated with liver fibrosis stages, and pathways related to extracellular exosomes and vesicles were implicated in fibrotic development. Consistently, in the Japanese and Germany cohorts, APOF, GSN, and LUM exhibited aberrant expression in both MASH patients and those with high NAS scores. CONCLUSIONS: The multi-cohort study identified specific serum protein signatures associated with MASL risk, which correspond to dysregulated gene expression patterns in hepatocytes. These findings bridge the gap between systemic circulatory changes and intrahepatic pathological progression, providing not only robust non-invasive biomarkers for early stratification but also potential mechanistically-driven therapeutic targets for halting the progression of MASLD.