The multifaceted role of ferroptosis in liver disease

Abstract

Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by excessive lipid peroxidation and associated with a plethora of pathological conditions in the liver. Emerging evidence supports the notion that dysregulated metabolic pathways and impaired iron homeostasis play a role in the progression of liver disease via ferroptosis. Although the molecular mechanisms by which ferroptosis causes disease are poorly understood, several ferroptosis-associated genes and pathways have been implicated in liver disease. Here, we review the physiological role of the liver in processing nutrients, our current understanding of iron metabolism, the characteristics of ferroptosis, and the mechanisms that regulate ferroptosis. In addition, we summarize the role of ferroptosis in the pathogenesis of liver disease, including liver injury, non-alcoholic steatohepatitis, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Finally, we discuss the therapeutic potential of targeting ferroptosis for managing liver disease.

Novel Insights in the Regulatory Mechanisms of Ferroptosis in Hepatocellular Carcinoma

“…Preventing chemotoxicity to healthy cells is a major concern in cancer treatment. Although inducing ferroptosis could be a reliable strategy for treating patients with HCC, emerging evidence also supports its role in the pathogenesis of other liver diseases ( Wu et al, 2021 ; Chen et al, 2022 ). Therefore, an in-depth understanding of the regulatory mechanisms of ferroptosis in healthy cells versus HCC cells is required to selectively attack cancer cells while protecting all healthy tissues.…”

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

“…However, in preclinical studies using mouse models of liver fibrosis or non-alcoholic steatohepatitis (NASH), the use of the lipophilic antioxidants Fer-1 and Lip-1 prevents disease progression [91]. However, unsatisfactory pharmacokinetics preclude their clinical application [92]. Potent Fer-1 analogues were synthesized by introducing structural modifications to the Fer-1 scaffold to improve solubility and stability and showed in vivo efficiency [93].…”

The Regulatory Roles of Polysaccharides and Ferroptosis-Related Phytochemicals in Liver Diseases

“…In the discovery of ferroptosis, either lipid peroxidation scavengers (i.e., ferrostatin-1) or iron chelators (i.e., deferoxamine) could specifically inhibit ferroptosis agonist (erastin or RSL3)-induced cell death, and therefore ferroptosis was characterized as a lipid-peroxidation-induced and iron-dependent cell death [ 113 , 114 , 115 ]. Ferroptosis serves as a major pathological mechanism in a wide range of organs, including the liver, heart, brain, and kidney [ 115 , 116 , 117 ]. In the past decade, the regulatory mechanisms of ferroptosis have been revealed ( Figure 1 ) but not fully elucidated.…”

“…The liver is one of the most important organs for iron storage. The hepatic iron and ROS burden are greater in the diseased liver than in the normal liver, suggesting that ferroptosis may be associated with chronic liver diseases [ 116 ]. Currently, ferroptosis has been identified as the key mechanism in NASH, ALD, ischemia/reperfusion, and iron overload (hemochromatosis)-related liver injury [ 118 , 140 , 141 , 142 , 143 ].…”