Unraveling the Role of BAG3 in Hepatic Fibrosis: Genetic and Biomarker Insights in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health burden, with hepatic fibrosis being the strongest determinant of clinical outcomes. While genetic variants such as <i>PNPLA3</i> and <i>TM6SF2</i> are recognized drivers of disease progression, the downstream molecular mediators linking genetic susceptibility to fibrogenesis remain unclear. This study investigated the role of the stress-response co-chaperone BAG3 as a circulating biomarker of hepatic fibrosis and its association with <i>PNPLA3</i> and <i>TM6SF2</i> genotypes. In a well-characterized Southern European cohort of 146 MASLD patients, liver fibrosis was assessed using the FIB-4 index, serum BAG3 levels were quantified by ELISA, and genotyping for <i>PNPLA3</i> and <i>TM6SF2</i> variants was performed. BAG3 concentrations were significantly higher in patients with advanced disease and correlated positively with FIB-4 values. Carriers of the <i>TM6SF2</i> risk allele exhibited increased BAG3 levels, and a cumulative increase was observed with multiple <i>PNPLA3</i> and <i>TM6SF2</i> risk alleles. These findings suggest that BAG3 may represent a potential, non-invasive biomarker reflecting fibrogenic burden and a mechanistic link between genetic risk and hepatic fibrosis in MASLD.