Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma

Abstract

Ferroptosis is a novel process of regulated cell death discovered in recent years, mainly caused by intracellular lipid peroxidation. It is morphologically manifested as shrinking of mitochondria, swelling of cytoplasm and organelles, rupture of plasma membrane, and formation of double-membrane vesicles. Work done in the past 5 years indicates that induction of ferroptosis is a promising strategy in the treatment of hepatocellular carcinoma (HCC). System xc-/GSH/GPX4, iron metabolism, p53 and lipid peroxidation pathways are the main focus areas in ferroptosis research. In this paper, we analyze the ferroptosis-inducing drugs and experimental agents that have been used in the last 5 years in the treatment of HCC. We summarize four different key molecular mechanisms that induce ferroptosis, i.e., system xc-/GSH/GPX4, iron metabolism, p53 and lipid peroxidation. Finally, we outline the prognostic analysis associated with ferroptosis in HCC. The findings summarized suggest that ferroptosis induction can serve as a promising new therapeutic approach for HCC and can provide a basis for clinical diagnosis and prevention of this disease.

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

“…Liver cancer (LC) is a lethal malignancy that aformulation of ferroptotic inducers is critical for improving safety by preventing unspecific side effects and effects people all over the world. Because of its rapid proliferation, and migration as well as chemoresistance, its progression is difficult to be controlled with existing treatment options, particularly at the advanced stage (metastasis), resulting in a low survival rate ( Li et al, 2022 ; Zhao et al, 2022 ). Consequently, finding an alternative remedies becomes a current concern.…”

“…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 ).…”

A new strategy for osteoarthritis therapy: Inhibition of glycolysis

“…Under anaerobic conditions, pyruvate is converted to lactate in the cytoplasm to regenerate NAD+, called anaerobic glycolysis ( Zheng et al, 2021 ). Lactate formation from pyruvate under normoxic conditions is known as aerobic glycolysis or the Warburg phenomenon ( Li et al, 2022a ). High-throughput glycolysis occurs primarily in the cytoplasm, and lactate production from pyruvate is driven by lactate dehydrogenase (LDH) ( Sotelo-Hitschfeld et al, 2012 ).…”

The ubiquitin‐specific protease 5 mediated deubiquitination of LSH links metabolic regulation of ferroptosis to hepatocellular carcinoma progression

“…13 In addition, extracts and monomers from natural products, including Chinese herbs, provide new strategies for the induction of ferroptosis to inhibit HCC. 14 Moreover, all these ferroptosis-targeting drugs induce ferroptosis of HCC cells mainly through iron metabolism, system xc−/GSH/glutathione peroxidase 4 (GPX4), p53, lipid peroxidation, and p62-Keap1-Nrf2 pathway. 15 Epigenetics, which determines gene transcription and has a significant impact on cell fate and developmental processes, mainly includes DNA methylation, histone modifications, noncoding RNAs, and chromatin remodeling.…”