TBBPA induced hepatocyte ferroptosis by PCBP1-mediated ferritinophagy

Abstract

Tetrabromobisphenol A (TBBPA) is the most widely used brominated flame retardant and has been identified as emerging widespread pollutants. Ferroptosis, a recently characterized form of iron-dependent cell death, is related to a wide range of liver diseases. Ferritinophagy as a novel selective form of autophagy functions in iron processing is essential to induce ferroptosis. Poly(rC)-binding protein 1 (PCBP1) is an iron chaperone involved in iron loading to ferritin. Nevertheless, the potential health risk caused by TBBPA in mammals is unknown. Thus, this study is conducted to explore the molecular mechanism of TBBPA-induced liver injury and the unique role of PCBP1 in it. In this study, we found that TBBPA exposure caused hepatic pathological injury and hepatocyte mitochondrial morphological changes, such as decreased or absent mitochondrial crest, ruptured mitochondrial membranes and mitochondrial shrinkage. The result showed that TBBPA exposure exacerbated glutathione depletion and lipid peroxidation, which are hallmarks of ferroptosis. Consistent with the results in vivo, TBBPA exposure activated ferritinophagy and upregulated indicators related to ferroptosis in hepatocytes. Of note, overexpression of PCBP1 inhibited TBBPA-induced ferroptosis by reducing overstimulated ferritinophagy. Here, we uncover a new mechanism whereby TBBPA triggers hepatocyte ferroptosis through the activation of ferritinophagy. Of note, we identify PCBP1 as critical for liver iron homeostasis, link this molecule to liver disease. Taken together, our findings provide a new therapeutic strategy and potential target for the treatment of liver disease.

Keywords: Ferritinophagy; Ferroptosis; Hepatocyte; PCBP1; TBBPA.