Distinct roles of the IRE1α arm and PERK arm of unfolded protein response in arachidonic acid-induced ferroptosis in hepatocytes

Abstract

Ferroptosis is a distinct form of cell death that is driven by iron-dependent phospholipid peroxidation. Polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (AA) and adrenal acid (AdA), are most prone to lipid peroxidation, which induces ferroptosis and affects the function of cell membranes. In this study, we discovered that AA induces ferritinophagy in hepatocytes, a selective form of autophagy that degrades ferritin, triggering unstable iron overload. Mechanistically, AA enhances cellular uptake of bound iron by up-regulating transferrin receptor 1 (TfR1). Additionally, AA induces endoplasmic reticulum stress (ER stress) and simultaneously activates two of its branches, pancreatic ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1). Notably, PERK and IRE1 appear to play distinct roles in inducing ferritinophagy. Inhibition of PERK reduced the AA-induced increase of Fe ²⁺ by alleviating ferritinophagy, while inhibition of IRE1 further exacerbated ferroptosis by activating ferritinophagy. Furthermore, there seems to be an interaction between the signaling pathways of ER stress, and inhibition of IRE1 exacerbates AA-induced ferritinophagy by further activating the PERK signaling pathway, thereby exacerbating the extent of cell death. Collectively, our findings suggest that iron overload is involved in AA-induced hepatocyte ferroptosis and that this process is regulated by ER stress-mediated ferritinophagy. This study suggests potential therapeutic strategies for treating liver diseases related to lipid metabolism disorders by intervening in the ferroptosis process.

Keywords

Hepatocyte / ER stress / Ferroptosis / Ferritinophagy / Polyunsaturated fatty