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

Abstract

Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading cause of cancer deaths worldwide. Diagnosis at an already late stage and general resistance to current therapies may be responsible for the dismal outcome. As the liver acts as a key factor in iron metabolism, ferroptosis is shown to play an important role in HCC carcinogenesis and, more importantly, may hold the potential to eradicate HCC. In this review, we summarize the current knowledge we have of the role of ferroptosis in HCC and the application of ferroptosis as a therapy option and provide an overview of the potential translation of ferroptosis in the clinical practice of HCC.

Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer

“…Consequently, finding an alternative remedies becomes a current concern. One of the effective therapeutic strategies is inducing ferroptosis, a new non-apoptotic form of regulated cell death which is characterized by iron accumulation-mediated lipid peroxidation propagation ( Bekric et al, 2022 ; Li et al, 2022 ). It is important to note that unselective induction of ferroptosis can also damage other healthy hepatic cells and tissues ( Bekric et al, 2022 ).…”

“…In response to ferroptosis, cancer cells upregulate and activate nuclear related factor 2 (Nrf2), a master regulator of antioxidant response that mediates transcription and expression of enzymatic and non-enzymatic antioxidants (including, glutathione (GSH) and glutathione peroxidase (GPX)4, respectively). It was found that GPX4 is overexpressed in advanced malignant stage in LC patients ( Bekric et al, 2022 ). This glutathione system is critical for protecting cancer cells against ferroptosis-dependent death via the detoxification activity of GPX4 for reducing lipid peroxides into their alcohols using GSH as a cofactor.…”

“…This glutathione system is critical for protecting cancer cells against ferroptosis-dependent death via the detoxification activity of GPX4 for reducing lipid peroxides into their alcohols using GSH as a cofactor. The latter itself can also reduce lipid peroxides ( Yang et al, 2020 ; Bekric et al, 2022 ). Thus, it is necessary to halt the antioxidant-mediated anti-ferroptotic response of cancer cells by combining F(II) NPs with a prooxidant agent (such as diethyldithiocarbamate, a metabolite of FDA-approved alcoholism remedy).…”

SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma

“…There is growing recognition that the induction of ferroptosis represents another promising strategy for combating cancer. While sorafenib is known for showing anti-angiogenic activities, it could also suppress HCC growth by inhibiting the cystine/glutamate antiporter system Xc − [ 27 , 28 ] and triggering ferroptosis. However, the underlying molecular machinery through which sorafenib inhibits the activity of system Xc − is largely undetermined.…”

“…Interestingly, we observed an increase in SLC7A11 expression following sorafenib treatment ( Figure 5 A,B) in both Huh7 and Hep3B cells, so we cannot rule out the possibility that the increased interaction between BECN1 and SLC7A11 was partially due to the enhanced expression of SLC7A11. The observation that sorafenib treatment upregulates the expression of SLC7A11 is noteworthy, as most reports indicate that sorafenib inhibits the activity of system Xc − [ 27 , 28 ]. Yuan et al also reported that sorafenib reduced the expression of SLC7A11 in hepatic stellate cells and alleviated liver fibrosis [ 45 ].…”