Discovering ferroptosis in biliary epithelium during liver fibrosis

Ferroptosis is an iron-dependent regulated cell death characterized by iron accumulation and lipid peroxidation. The liver represents the primary site of iron-overload injury due to its role in iron metabolism, but the potential role of ferroptosis in the biliary epithelium is yet unknown. The study investigated the recruitment of ferroptosis under control conditions and after bile duct ligation (BDL), highlighting the effects of ferroptosis inducers and inhibitors in a cell line of cholangiocytes. In addition, we identified iron deposits through Perls Prussian blue as well as the presence of proteins such as ferritin, transferrin receptor 1 (CD71), glutathione peroxidase-4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4). The results showed an increase in the expression of ferritin, CD71 and ACSL4 in the BDL model, whereas GPX4 was reduced in the cholestatic model in comparison to the control. In addition, sorafenib failed to trigger ferroptosis in cholangiocytes, whereas erastin was a potent inducer. Conversely, ferrostatin-1 (Fer-1) did not inhibit ferroptosis, while β-mercaptoethanol (βME) could protect cholangiocytes from ferroptosis-induced cell death. All these findings are important for understanding the involvement of ferroptosis in cholangiocyte pathophysiology and may support additional studies regarding the possible application of ferroptosis modulators in the treatment of liver fibrosis.