Ferroptosis causes pancreatic failure in a mouse model of non-HFE hemochromatosis (FpnC326S)

The non-HFE hemochromatosis Ferroportin(C326S) mice develop similar degrees of hepatic and pancreatic iron accumulation, associated with lipid peroxidation. However, in contrast to the liver, the pancreas is severely damaged by iron-overload, leading to exocrine pancreatic failure and early death. The underlying mechanisms and organ selectivity of tissue damage observed in these mice remain poorly understood. Of note, iron restriction prevents these complications, suggesting that ferroptosis explains exocrine pancreatic failure. We aimed to understand whether tissue iron-overload is sufficient to cause ferroptosis in FpnC326S mice and which mechanisms protect or sensitize tissues to ferroptosis. We demonstrate that the pancreas, unlike the liver, shows several ferroptosis hallmarks: accumulation of the lipid peroxidation product 4-HNE, ultrastructural mitochondrial changes, increased expression of the ferroptosis-related genes Chac1 and Acsl4. RNAseq data suggest that iron overload in the pancreas is due to low ferroportin expression, while in the liver it is related to the high expression of NTBI importers. Additionally, iron overload may be more toxic in the pancreas as the organ is poorly equipped with antioxidant defences. Preliminary lipidomic analyses indicate organ-specific changes in lipid composition possibly contributing to the sensitivity/resistance to ferroptosis. To understand the chronology of the exocrine pancreatic failure, we performed histological analyses of tissues at different ages. We find that early pancreatic iron accumulation triggers lipid peroxidation. Consistent with the reported ferroptosis immunogenicity, we observe subsequent massive macrophage infiltration. Overall, our data are expected to discover novel therapeutic mechanisms that protect tissues from iron-mediated toxicity and ferroptosis in iron overload disorders.