Fibulin Family Members: New Players in Liver Fibrosis and Potential Biomarkers in Chronic Liver Diseases

Chronic liver diseases (CLD) arising from various etiologies including viral hepatitis, excessive alcohol intake, alcoholic associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), are associated with persistent hepatic injury ultimately resulting in fibrosis. Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM). This pathological ECM deposition increases tissue stiffness, disrupts normal tissue architecture and impairs liver functions leading to cirrhosis which constitutes a major risk factor for the onset of hepatocellular carcinoma (HCC). The characteristics of the ECM in liver fibrosis have been extensively investigated, particularly with the use of recent proteomic approaches that provide a large overview of ECM changes during disease progression. Alongside large collagen fiber molecules, established as a hallmark of fibrotic tissues, numerous other matrix components are significantly altered. These include the fibulin family. These glycoproteins are distributed across various tissues and involved in numerous physiological processes including embryonic development and tissue repair. They are implicated in a range of pathological processes such as hypertrophic cardiomyopathy, chronic fibrotic disorders, and cancer. In healthy a liver, low levels of fibulins can be detected; however, the expression of a number of fibulin family members is markedly induced during the progression of fibrosis. Beyond their role in the organization and structure integrity of elastic fibers, their contribution to the pathogenesis of liver fibrosis and HCC remains poorly understood. The present review provides an up-to-date overview of the literature on fibulins in the context of chronic liver diseases with particular insights from new omics meta-analyses.