Effects of regulated cell death (e. g. ferroptosis) on early hepatic ischemia reperfusion damage in steatotic donor organs

Introduction During ischemia-reperfusion, regulated cell death (RCD) signaling pathways, mainly ferroptosis, are activated. In this iron-dependent form of RCD, reactive oxygen species accumulate in the cell and eventually lead to cell death. Due to shortage of donor organs, more steatotic livers are transplanted, possibly showing increased susceptibility to ischemia-reperfusion injury (IRI). Therefore, this study explores the effect of cell death mechanisms (particularly ferroptosis) on early IRI in steatotic donor livers.

Material and Methods In this study, an in vitro model of IRI was established in marginal organs. For ischemia, human HepaRG cells were hypoxically treated for 48h. Subsequently, a simulation of reperfusion followed. Differences between untreated liver cell lines and steatotic liver cells were examined, by detecting specific cell death signaling pathways (apoptosis, necroptosis and ferroptosis). Furthermore, human liver biopsies were examined before and after reperfusion.

Results In the in vitro model, significant differences in the expression of cell death-specific markers were detected between steatotic and non-steatotic liver cells.

Human graft biopsies show significant tissue damage (HE section) and differences in cell death expression, especially with respect to ferroptosis, between marginal and non-marginal donor organs.

Conclusion Ferroptosis appears to be an initial activator of hepatic IRI and affects mainly marginal organs, leading to a dramatic increase in post-translational damage. Therefore, inhibition of ferroptosis opens new therapeutic opportunities to improve liver transplantation outcomes.

Publication History

Article published online:
26 January 2022