Integrative Multi-Omics Analysis Identifies Stellate Cell-Derived Complement Component 7 as a Predictor of Fibrosis and Liver-Related Events in MASLD Patients

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden, with advanced fibrosis and liver-related events (LREs) being key prognostic factors. However, existing non-invasive biomarkers insufficiently capture both fibrosis severity and LRE risk. This study aimed to identify a mechanistically grounded biomarker for clinical risk stratification. METHODS: We performed an integrative multi-omics analysis using publicly available hepatic transcriptomic and plasma proteomic datasets together with in-house spatial transcriptomic analyses, followed by validation in three MASLD cohorts: biopsy-confirmed Japanese (n = 430), VCTE-based (n = 120), and UK Biobank (n = 4,486) cohorts. LRE risk was assessed using Kaplan-Meier and Cox regression analyses. Single-nucleus RNA sequencing (snRNA-seq), in situ hybridization (ISH), and in vitro assays using hepatic stellate cells (HSCs) were performed to assess molecular localization and functional relevance. RESULTS: Complement component 7 (C7) was consistently identified as a top candidate. Spatial transcriptomics and ISH localized C7 expression to activated HSCs within fibrotic regions. Serum C7 levels strongly correlated with fibrosis stage and liver stiffness. A threshold ≥140 μg/mL predicted significantly higher LRE risk and remained independently predictive (HR 4.54, 95% CI 1.49-13.82). C7 outperformed FIB-4, autotaxin, APRI, FAST, and AAR in AUROC analysis (0.90 vs. 0.85, 0.84, 0.77, 0.75, 0.67). External validation in UK Biobank supported these findings. Spatial module-score analyses linked C7-enriched regions to ECM/HSC-related fibrogenic programs and progenitor/ductular reaction signatures. C7 knockdown in LX-2 cells suppressed extracellular matrix genes including LAMA2, LAMB1, and COL6A3. CONCLUSIONS: C7 is a mechanistically supported, non-invasive biomarker that surpasses conventional indices in predicting fibrosis and LREs in MASLD. These findings highlight complement-mediated fibrogenesis and suggest C7 as a promising tool for clinical risk stratification. IMPACT AND IMPLICATIONS: This study identifies complement component 7 (C7) as a non-invasive biomarker associated with fibrosis severity and liver-related events in MASLD through an integrative multi-omics approach. C7 was linked to HSC-rich fibrotic niches, extracellular matrix remodeling, and future liver-related risk, with external validation in the UK Biobank cohort. These findings suggest that serum C7 may improve risk stratification by capturing both fibrosis burden and clinically relevant disease progression in MASLD.