The Emerging Role of Ferroptosis in Liver Diseases

Abstract

Ferroptosis is a newly discovered type of cell death mediated by iron-dependent lipid peroxide. The disturbance of iron metabolism, imbalance of the amino acid antioxidant system, and lipid peroxide accumulation are considered distinct fingerprints of ferroptosis. The dysregulation of ferroptosis has been intensively studied in recent years due to its participation in various diseases, including cancer, kidney injury, and neurodegenerative diseases. Notably, increasing evidence indicates that ferroptosis plays different roles in a wide spectrum of liver diseases. On the one hand, inhibiting ferroptosis may counteract the pathophysiological progression of several liver diseases, such as alcoholic liver injury, nonalcoholic steatosis hepatitis and fibrosis. On the other hand, inducing ferroptosis may restrict the emergence of secondary resistance to current medicines, such as sorafenib, for hepatocellular carcinoma (HCC) therapy. Here, we summarize the biological characteristics and regulatory signalling pathways of ferroptosis involved in liver disease. The current available medical agents targeting ferroptosis, including inducers or inhibitors applied in liver diseases, are also reviewed. This work aims to provide new insight into the emerging role of pathogenesis and therapeutic approaches for liver diseases.

Network Pharmacology Identifies Therapeutic Targets and the Mechanisms of Glutathione Action in Ferroptosis Occurring in Oral Cancer

“…In the present study, we investigated the possible use of GSH in treating OC by targeting ferroptosis. Ferroptosis, a newly discovered type of cell death mediated by iron-dependent lipid peroxidation ( Chen S. et al, 2021 ), is reported to be a promising approach in cancer therapy ( Tang et al, 2021b ). Oral squamous cell carcinoma was shown to have a ferroptosis-specific gene-expression signature, suggesting ferroptosis regulation may be clinically relevant for combination therapies ( Gu et al, 2021 ).…”

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

“…Thus, MT-1G pathway inhibition enhances the ferroptosis-inducing activity of sorafenib. Similarly, expression levels of the retinoblastoma (RB) protein that acts as a negative regulator of cell proliferation impacts the response of HCC cells to sorafenib and the regulation of ferroptosis [165]. Liver cancer cells with reduced RB levels show a 2~3 times higher cell mortality upon exposure to sorafenib than control cells with normal RB levels [166].…”

“…The glycoprotein ceruloplasmin (CP) has been discovered to play a suppressing role in HCC cells by regulating iron homeostasis [227]. Depletion of CP significantly increased the accumulation of intracellular ferrous iron (Fe 2+ ) and lipid ROS, promoting erastin-and RSL3-induced ferroptosis [165].…”

Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

“…As summarized by Tang and Kroemer [ 9 ], other hypotheses include either currently unknown pore-forming proteins activated by post-translational modifications or altered subcellular localization, the release of lysosomal hydrolases followed by the destruction of plasma membrane components or a deranged phospholipid bilayer (a)symmetry induced by flippases or scramblases that might compromise membrane function and integrity. As the molecular mechanisms of ferroptosis have been intensively investigated in recent years, ferroptosis has more and more become a possible and innovative therapeutic strategy against different human diseases especially liver diseases (including ischemia/reperfusion-related injury, nonalcoholic fatty and alcoholic liver diseases, hemochromatosis to drug-injured liver injury) and in HCC as reviewed recently in detail [ 1 , 33 , 36 , 37 ].…”