Ferroptosis in COVID-19-related liver injury: A potential mechanism and therapeutic target

Abstract

The outbreak and worldwide spread of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a threat to global public health. SARS-CoV-2 infection not only impacts the respiratory system but also causes hepatic injury. Ferroptosis, a distinct iron-dependent form of non-apoptotic cell death, has been investigated in various pathological conditions, such as cancer, ischemia/reperfusion injury, and liver diseases. However, whether ferroptosis takes part in the pathophysiological process of COVID-19-related liver injury has not been evaluated yet. This review highlights the pathological changes in COVID-19-related liver injury and presents ferroptosis as a potential mechanism in the pathological process. Ferroptosis, as a therapeutic target for COVID-19-related liver injury, is also discussed. Discoveries in these areas will improve our understanding of strategies to prevent and treat hepatic injuries caused by COVID-19.

Keywords: COVID-19; SARS-CoV-2; ferroptosis; hyperferritinemia; liver.

Figure 1

The potential link between ferroptosis and COVID-19-related liver injury. SARS-CoV-2 recognizes the angiotensin-converting enzyme 2 receptor in the alveoli, especially type II alveolar cells. SARS-CoV-2 subsequently reaches the blood circulation through the damaged blood–air barrier. Next, SARS-CoV-2 further infects the liver. After the infection, a plethora of transferrins carrying Fe³⁺ is transferred into the cell through transferrin receptor1. Eventually, Fe³⁺ is transformed to Fe²⁺ by STEAP family member 3, in addition to the Fe²⁺ degraded from excessive ferritin by nuclear receptor coactivator 4—contributing to the accumulation of ferrous iron in the cell. Numerous cytokines are also released during the infection, stimulating hepcidin expression, suppressing ferroportin, and aggravating the accumulation of iron even more. On the other hand, SARS-CoV-2 decreases the expression of GPX4, facilitating the iron overload-induced Fenton reaction, accompanied by polyunsaturated fatty acids, and producing massive amounts of lipid reactive oxygen species. Ultimately, ferroptosis occurs and causes liver injury.