Liver injury in COVID-19: Holds ferritinophagy-mediated ferroptosis accountable

Abstract

Even in patients without a history of liver disease, liver injury caused by coronavirus disease 2019 (COVID-19) is gradually becoming more common. However, the precise pathophysiological mechanisms behind COVID-19's liver pathogenicity are still not fully understood. We hypothesize that inflammation may become worse by cytokine storms caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Elevated ferritin levels can initiate ferritinophagy mediated by nuclear receptor coactivator 4 (NCOA4), which leads to iron elevation, and ferroptosis. In COVID-19 patients, ferroptosis can be restricted to reduce disease severity and liver damage by targeting NCOA4-mediated ferritinophagy. To confirm the role of ferritinophagy-mediated ferroptosis in SARS-CoV-2 infection, further research is required.

Keywords: COVID-19; Ferritinophagy; Ferroptosis; Iron; Liver injury; SARS-CoV-2.

Figure 1

Proposed mechanism of ferritinophagy-mediated ferroptosis in severe acute respiratory syndrome coronavirus 2 infection-induced liver injury. High levels of inflammation characterized by cytokine storms are caused by severe acute respiratory syndrome coronavirus 2 infection. These cytokine storms cause hyper-ferritinemia by stimulating hepatocytes to secrete ferritin and upregulate hepcidin levels, which further amplifies inflammation. The nuclear receptor coactivator 4 binds to ferritin and delivers it to autophagosomes for ferritin degradation and iron release. Ferroptosis is generated by the excess of intracellular iron, consequently resulting in liver injury. The death of hepatocytes further releases ferritin. Thus, the mutual promotion of ferritin and hepatocyte damage generates a vicious loop that constantly heightens liver injury.