Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver-related morbidity and mortality worldwide. As the disease progresses, liver fibrosis and liver-related events (LREs), including hepatocellular carcinoma and other complications, become important indicators of clinical risk. However, accurately assessing fibrosis severity and predicting future LREs remains challenging. Liver biopsy is invasive and costly, while existing non-invasive biomarkers and imaging approaches have limitations.
To address these challenges, a research team led by Dr. Takefumi Kimura, together with Dr. Shohei Kondo, Dr. Takanobu Iwadare, and Dr. Naoki Tanaka from Shinshu University, Japan, investigated potential biomarkers of fibrosis and disease progression. This paper was made available online on July 21, 2026, and will be published in Volume 8, Issue 11 of the journal JHEP Reports on November 01, 2026. The researchers used an integrative multi-omics approach to investigate complement C7 as a potential biomarker of fibrosis and liver-related events in MASLD.
According to Dr. Kimura, "This study identified complement C7 as a novel biomarker associated with fibrosis progression and LREs in MASLD using a comprehensive multi-omics approach."
The researchers evaluated C7 across independent cohorts, including 430 patients with biopsy-confirmed MASLD, 120 patients assessed using vibration-controlled transient elastography (VCTE), and 4,486 UK Biobank participants. Serum C7 levels were associated with fibrosis stage and liver stiffness. A serum C7 threshold of 140 μg/mL was also associated with higher LRE incidence. After adjustment for other factors, elevated C7 remained independently associated with LREs, with a hazard ratio of 4.54 (95% confidence interval, 1.49–13.82).
C7 achieved an area under the receiver operating characteristic curve of 0.90 for detecting LREs in the VCTE cohort, compared with 0.85 for fibrosis-4 index (FIB-4), 0.84 for autotaxin, 0.77 for aspartate aminotransferase to platelet ratio index (APRI), 0.75 for FibroScan-AST (FAST), and 0.67 for aspartate aminotransferase-to-alanine aminotransferase ratio (AAR). These findings were further supported by external validation in the UK Biobank cohort.
The multi-omics analyses also localized C7 expression to activated hepatic stellate cells within fibrotic liver regions. Single-nucleus RNA sequencing identified hepatic stellate cells as an important source of C7, while C7 expression was associated with extracellular matrix (ECM) organization and fibrogenic pathways. In cultured LX-2 hepatic stellate cells, small interfering RNA (siRNA)-mediated C7 knockdown reduced expression of ECM-related genes, including LAMA2, LAMB1, and COL6A3.
Dr. Kimura further highlighted the study design, stating, "The major strength of this study lies in its integrative, multi-omics design that incorporates transcriptomics, proteomics, spatial and single-cell analyses, as well as in vitro functional validation."
The findings suggest that measuring serum C7 could provide information about both fibrosis burden and clinically relevant disease progression. In the large population affected by MASLD, such a biomarker could potentially help narrow down patients at higher risk and support non-invasive risk stratification. However, the study does not establish that C7 directly causes liver fibrosis or LREs. Differences between study cohorts may also affect generalizability, while in vivo experiments are needed to establish causality. Prospective studies are also required to determine the clinical utility of C7 for long-term risk stratification and monitoring.
Looking ahead, Dr. Kimura noted, "Serum C7 holds promise as a non-invasive biomarker for stratifying fibrosis severity and predicting clinical outcomes in MASLD."
Taken together, these results provide a multi-layered basis for further investigation of C7 as a potential tool for non-invasive assessment and risk stratification in MASLD. The findings also provide new insight into the relationship between hepatic stellate cell-derived C7, fibrotic liver regions, and extracellular matrix remodeling.
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