Motta_2025_Int.J.Mol.Sci_26_

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 PNPLA3 and TM6SF2 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 PNPLA3 and TM6SF2 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 PNPLA3 and TM6SF2 variants was performed. BAG3 concentrations were significantly higher in patients with advanced disease and correlated positively with FIB-4 values. Carriers of the TM6SF2 risk allele exhibited increased BAG3 levels, and a cumulative increase was observed with multiple PNPLA3 and TM6SF2 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.