Novel Insights in the Regulatory Mechanisms of Ferroptosis in Hepatocellular Carcinoma

Ma, Shiwen; Adzavon, Yao Mawulikplimi; Wen, Xin; Zhao, Pengxiang; Xie, Fei; Liu, Mengyu; Ma, Xiu-Wen

doi:10.3389/fcell.2022.873029

Cited by 9 publications

(8 citation statements)

References 140 publications

(180 reference statements)

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“…9 Ferroptosis is regulated by specific pathways, which mainly include iron homeostasis, ROS homeostasis, lipid metabolism, and glutathione metabolism. 10 Previous research has found that fluoride could result in the disordered arrangement of hepatocytes, infiltration of inflammatory cells, lysis or fragmentation of cells, increase in the number of lipid droplets, and mitochondrial damage and reduction. 11 Moreover, fluoride could increase the activities of AST, ALT, ALP, and LDH and elevate the levels of ROS in the liver, 5 which could oxidize unsaturated fatty acids, induce the production of lipid peroxidation, and ultimately damage the structure and function of hepatocytes.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The main ultrastructural features of ferroptosis are smaller mitochondria, increased membrane density, decreased/disappeared cristae density, plasma membrane blebbing, and increased cytoplasmic and lipid peroxidation . Ferroptosis is regulated by specific pathways, which mainly include iron homeostasis, ROS homeostasis, lipid metabolism, and glutathione metabolism . Previous research has found that fluoride could result in the disordered arrangement of hepatocytes, infiltration of inflammatory cells, lysis or fragmentation of cells, increase in the number of lipid droplets, and mitochondrial damage and reduction .…”

Section: Introductionmentioning

confidence: 99%

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α-Lipoic Acid Alleviated Fluoride-Induced Hepatocyte Injury via Inhibiting Ferroptosis

Zhao

Liu

Liang

et al. 2022

J. Agric. Food Chem.

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Fluoride is widely used in agricultural production and food packaging. Excessive fluoride in water and food is a serious threat to liver health. α-Lipoic acid, a natural free radical scavenger, has hepatoprotective properties. However, the protective effect of α-lipoic acid on fluorohepatotoxicity is uncertain. The aim of this study was to investigate the mechanism of ferroptosis in α-lipoic acid preventing fluoride-induced hepatotoxicity. Five-week-old ICR mice were treated with sodium fluoride (100 mg/L) and/or α-lipoic acid (200 mg/kg) for 9 weeks. The results showed that α-lipoic acid attenuated fluoride-induced damage to liver morphology and ultrastructure. Moreover, α-lipoic acid alleviated fluoride-induced iron accumulation, increased oxidative stress, and elevated lipid peroxidation in the liver. In addition, the mechanism study found that α-lipoic acid prevented fluoride-induced ferroptosis through the System Xc–/GPX4 axis, lipid peroxidation axis, and iron metabolism axis, but it was interestingly not regulated by mitochondrial free radical axis in the hepatocytes. Altogether, this study indicated that α-lipoic acid prevents fluoride-induced liver injury by inhibiting ferroptosis, which has potential implications for the prevention and treatment of fluoride-induced liver injury.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

α-Lipoic Acid Alleviated Fluoride-Induced Hepatocyte Injury via Inhibiting Ferroptosis

Zhao

Liu

Liang

et al. 2022

J. Agric. Food Chem.

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“…Recent studies have also indicated that FAK may regulate proliferation, survival and angiogenesis of cancer cells, and function as a prognostic indicator of HCC [ 17 ]. In addition, various anti-cancer drugs such as sorafenib may regulate intracellular iron metabolism and lipid peroxidation to promote ferroptosis in HCC cells, which has become a new therapeutic strategy for the treatment of HCC [ 18 , 19 ]. Functional modules of amino acid metabolism included glutathione metabolism, and cysteine and methionine metabolism-related pathways.…”

Section: Resultsmentioning

confidence: 99%

Pien-Tze-Huang prevents hepatocellular carcinoma by inducing ferroptosis via inhibiting SLC7A11-GSH-GPX4 axis

Yan

Liu

et al. 2023

Cancer Cell Int

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Background Malignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was to evaluate anti-cancer efficacy of Pien-Tze-Huang (PZH), and to investigate the underlying mechanisms by integrating transcriptional regulatory network analysis and experimental validation. Methods A diethylnitrosamine (DEN)-induced HCC model in rats was established and used to evaluate the anti-cancer efficacy of PZH. After detecting a transcriptomic profiling, the “disease-related gene–drug effective target” interaction network was constructed, and the candidate targets of PZH against malignant transformation from hepatic fibrosis to HCC were identified and verified in vitro. Results PZH effectively alleviated the pathological changes of hepatic fibrosis and cirrhosis, and inhibited tumor formation and growth in DEN-induced HCC rats. Additionally, the administration of PZH reduced the levels of various hepatic function-related serological indicators significantly. Mechanically, a ferroptosis-related SLC7A11-GSH-GPX4 axis might be one of potential targets of PZH against malignant transformation from hepatic fibrosis to HCC. Especially, high SLC7A11 expression may be associated with poor prognosis of HCC patients. Experimentally, the administration of PZH markedly increased the trivalent iron and ferrous ion, suppressed the expression levels of SLC7A11 and GPX4 proteins, and reduced the GSH/GSSG ratio in the liver tissues of DEN-induced HCC rats. Conclusions Our data offer an evidence that PZH may effectively improve the hepatic fibrosis microenvironment and prevent the occurrence of HCC through promoting ferroptosis in tumor cells via inhibiting the SLC7A11-GSH-GPX4 axis, implying that PZH may be a potential candidate drug for prevention and treatment of HCC at an early stage.

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“…For example, combination therapies of chelators or chelators with other anticancer agents could be used in initiating ferroptosis in relation to drug resistance to established therapies. In these cases, the regulation of ferroptosis appears to offer therapeutic solutions for refractory and recurring tumors in almost all types of cancer, metastasis and drug resistance [143][144][145][146][147][148][149][150][151]. In other cases, such as in therapeutic combination with immunotherapy, ferroptosis can be enhanced and improve the efficacy of immunotherapy [152][153][154].…”

Section: Ferroptosis the New Target In Cancer Therapies And The Role ...mentioning

confidence: 99%

New Iron Metabolic Pathways and Chelation Targeting Strategies Affecting the Treatment of All Types and Stages of Cancer

Kontoghiorghes¹

2022

IJMS

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There is new and increasing evidence from in vitro, in vivo and clinical studies implicating the pivotal role of iron and associated metabolic pathways in the initiation, progression and development of cancer and in cancer metastasis. New metabolic and toxicity mechanisms and pathways, as well as genomic, transcription and other factors, have been linked to cancer and many are related to iron. Accordingly, a number of new targets for iron chelators have been identified and characterized in new anticancer strategies, in addition to the classical restriction of/reduction in iron supply, the inhibition of transferrin iron delivery, the inhibition of ribonucleotide reductase in DNA synthesis and high antioxidant potential. The new targets include the removal of excess iron from iron-laden macrophages, which affects anticancer activity; the modulation of ferroptosis; ferritin iron removal and the control of hyperferritinemia; the inhibition of hypoxia related to the role of hypoxia-inducible factor (HIF); modulation of the function of new molecular species such as STEAP4 metalloreductase and the metastasis suppressor N-MYC downstream-regulated gene-1 (NDRG1); modulation of the metabolic pathways of oxidative stress damage affecting mitochondrial function, etc. Many of these new, but also previously known associated iron metabolic pathways appear to affect all stages of cancer, as well as metastasis and drug resistance. Iron-chelating drugs and especially deferiprone (L1), has been shown in many recent studies to fulfill the role of multi-target anticancer drug linked to the above and also other iron targets, and has been proposed for phase II trials in cancer patients. In contrast, lipophilic chelators and their iron complexes are proposed for the induction of ferroptosis in some refractory or recurring tumors in drug resistance and metastasis where effective treatments are absent. There is a need to readdress cancer therapy and include therapeutic strategies targeting multifactorial processes, including the application of multi-targeting drugs involving iron chelators and iron–chelator complexes. New therapeutic protocols including drug combinations with L1 and other chelating drugs could increase anticancer activity, decrease drug resistance and metastasis, improve treatments, reduce toxicity and increase overall survival in cancer patients.

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Novel Insights in the Regulatory Mechanisms of Ferroptosis in Hepatocellular Carcinoma

Cited by 9 publications

References 140 publications

α-Lipoic Acid Alleviated Fluoride-Induced Hepatocyte Injury via Inhibiting Ferroptosis

α-Lipoic Acid Alleviated Fluoride-Induced Hepatocyte Injury via Inhibiting Ferroptosis

Pien-Tze-Huang prevents hepatocellular carcinoma by inducing ferroptosis via inhibiting SLC7A11-GSH-GPX4 axis

New Iron Metabolic Pathways and Chelation Targeting Strategies Affecting the Treatment of All Types and Stages of Cancer

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