Fibulin-3 as a reliable biomarker of fibrosis in obese subjects with Metabolically Dysfunction Associated Steatotic Liver Disease

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Abstract
Introduction and Objectives: Metabolic dysfunction associated steatotic liver disease (MASLD) affects about one quarter of adults worldwide, and liver fibrosis is its strongest predictor of liver related morbidity and mortality. Using combined in-silico screening and clinical validation, we aimed to identify circulating biomarkers associated with fibrosis progression. Fibulin 3 was identified, and its diagnostic performance was evaluated in biopsy proven MASLD cohorts. Materials and Methods: The GSE125251 RNAseq dataset was reanalyzed to compare liver transcriptomes from MASLD subjects with minimal (F0/F1) versus moderate to advanced fibrosis (F2/F3, F4). Differentially expressed genes (DEGs) were filtered to retain plasma secreted, protein coding candidates. Top ranked genes were evaluated in liver biopsies from a morbidly obese cohort (n = 65) stratified by fibrosis stage, and their plasma levels were measured via ELISA in an independent bariatric cohort (n = 225). Results: Among 106 DEGs, 22 encoded plasma circulating proteins. Six top candidates (EFEMP1, LTBP2, LUM, DPT, CHI3L1, CCL20) were prioritized. EFEMP1 (Fibulin 3) showed the strongest association with fibrosis, with significantly higher hepatic mRNA and protein expression in F2/F3, F4 versus F0 F1 (p < 0.005). Plasma Fibulin 3 levels correlated with fibrosis stage (ρ = 0.40, p < 0.0001), increasing from 9.4 ng/mL in F0F1 to 21.7 ng/mL in F2/F3,F4. Its diagnostic performance for F ≥ 2 (AUROC = 0.78) exceeded that of APRI, FIB-4, NFS, and HSI. A combined index including Fibulin 3, HSI, platelets, and GGT increased the AUROC to 0.87 (CI: 0.79 0.92). Conclusions: Plasma Fibulin 3 is notably higher in individuals with advanced MASLD and represents a promising non-invasive biomarker for liver fibrosis stratification in metabolically unhealthy obese populations.

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