Dihydroartemisinin Induces Ferroptosis in HCC by Promoting the Formation of PEBP1/15‐LO

Su, Ying; Zhao, Danli; Jin, Chen; Li, Zhanghao; Sun, Sumin; Xia, Siwei; Zhang, Yuxin; Zhang, Zili; Zhang, Feng; Xu, Xuefen; Zhang, Biyun; Zheng, Shizhong

doi:10.1155/2021/3456725

Cited by 37 publications

(26 citation statements)

References 43 publications

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“…A variety of factors can induce HCC; however, most HCCs are associated with hepatitis B virus infection, especially in China ( 2 ). Surgery is the first-line treatment for HCC ( 3 ). Yet, due to the lack of early specific symptoms, most patients are diagnosed at the middle or advanced stage, thus missing the opportunity for surgical treatment ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

OIT3 serves as a novel biomarker of hepatocellular carcinoma by mediating ferroptosis via regulating the arachidonic acid metabolism

Wen

Aili²,

Yan³

et al. 2022

Front. Oncol.

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BackgroundOncoprotein-Induced Transcript 3 Protein (OIT3) was identified as a liver-specific gene with abnormal expression in hepatocellular carcinoma (HCC). Herein, we aimed to examine the function and specific mechanism of OIT3 in HCC.MethodsBioinformatic analyses and tissue microarray via immunohistochemistry were used to validate the expression of OIT3 in HCC. The biofunctions of OIT3 in HCC were determined in vitro and in vivo. The mechanism was confirmed by RNA-Sequence and Western blotting. The uni- and multivariate analyses were used to identify the independent predictors for HCC.ResultsLow expression of OIT3 was observed in HCC and predicted a poor clinical outcome. Ectopic expression of OIT3 could inhibit the proliferation, migration, and invasion abilities of HCC cells. Mechanistically, OIT3 upregulated the expression of ALOX15 and CYP4F3, thus inducing arachidonic acid increase, ROS accumulation, and lipid peroxidation, and eventually causing ferroptosis. OIT3 was validated as a prognostic predictor for HCC patients.ConclusionsOur findings revealed a novel role of OIT3 in the process of tumorigenesis of HCC. OIT3 inhibited reproliferation, migration, and invasion of HCC cells by triggering ferroptosis, which indicates that OIT3 could serve as a potential biomarker in HCC.

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Section: Introductionmentioning

confidence: 99%

OIT3 serves as a novel biomarker of hepatocellular carcinoma by mediating ferroptosis via regulating the arachidonic acid metabolism

Wen

Aili²,

Yan³

et al. 2022

Front. Oncol.

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“…[167] proved artesunate to be an effective and specific ferroptosis activator as well as a novel pathway for killing pancreatic cancer cells. In HCC cells, another derivate of artemisinim, dihydroartemisinin (DHA), was shown to induce ROS accumulation and thus ferroptosis, leading to reduced HCC development in a dose-dependent manner both in vitro and in vivo [206]. Recently, a synergistic mode of action was also proven for the combined treatment of sorafenib and artesunate in HCC cell lines in vitro and in vivo [207].…”

Section: Other Classesmentioning

confidence: 99%

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

Kusnick

Bruneau

Tacke

et al. 2022

Immuno

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Ferroptosis is a recently recognized iron-dependent form of non-apoptotic regulated cell death (RCD) characterized by lipid peroxide accumulation to lethal levels. Cancer cells, which show an increased iron dependency to enable rapid growth, seem vulnerable to ferroptosis. There is also increasing evidence that ferroptosis might be immunogenic and therefore could synergize with immunotherapies. Hepatocellular carcinoma (HCC) is the most common primary liver tumor with a low survival rate due to frequent recurrence and limited efficacy of conventional chemotherapies, illustrating the urgent need for novel drug approaches or combinatorial strategies. Immunotherapy is a new treatment approach for advanced HCC patients. In this setting, ferroptosis inducers may have substantial clinical potential. However, there are still many questions to answer before the mystery of ferroptosis is fully unveiled. This review discusses the existing studies and our current understanding regarding the molecular mechanisms of ferroptosis with the goal of enhancing response to immunotherapy of liver cancer. In addition, challenges and opportunities in clinical applications of potential candidates for ferroptosis-driven therapeutic strategies will be summarized. Unraveling the role of ferroptosis in the immune response could benefit the development of promising anti-cancer therapies that overcome drug resistance and prevent tumor metastasis.

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“…For instance, magnesium isoglycyrrhizinate, derivatives of artemisinin (such as artemether, artesunate, and dihydro-artemisinin (DHA)), wild bitter melon extracts, chrysophanol, and zalkaloid berberine could block the development of liver fibrosis by triggering HSC ferroptosis [ 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 ]. Besides, several studies revealed that DHA could trigger ferroptosis to block HCC growth by promoting PEBP1/15LO formation or an unfolded protein response [ 153 , 154 ]. Moreover, DHA and artesunate could enhance the anti-tumor efficacy of sorafenib on HCC by inducing ferroptosis [ 155 , 156 ].…”

Section: Cell Death In Liver Diseasesmentioning

confidence: 99%

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

Ren

Song

et al. 2022

Nutrients

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Liver disease is a global health burden with high morbidity and mortality worldwide. Liver injuries can develop into severe end-stage diseases, such as cirrhosis or hepatocellular carcinoma, without valid treatment. Therefore, identifying novel drugs may promote liver disease treatment. Phytochemicals, including polysaccharides, flavonoids, alkaloids, and terpenes, are abundant in foods and medicinal plants and have various bioactivities, such as antioxidation, immunoregulation, and tumor killing. Recent studies have shown that many natural polysaccharides play protective roles in liver disease models in vitro and in vivo, such as fatty liver disease, alcoholic liver disease, drug-induced liver injury, and liver cancer. The mechanisms of liver disease are complex. Notably, ferroptosis, a new type of cell death driven by iron and lipid peroxidation, is considered to be the key mechanism in many hepatic pathologies. Therefore, polysaccharides and other types of phytochemicals with activities in ferroptosis regulation provide novel therapeutic strategies for ferroptosis-related liver diseases. This review summarizes our current understanding of the mechanisms of ferroptosis and liver injury and compelling preclinical evidence of natural bioactive polysaccharides and phytochemicals in treating liver disease.

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Dihydroartemisinin Induces Ferroptosis in HCC by Promoting the Formation of PEBP1/15‐LO

Cited by 37 publications

References 43 publications

OIT3 serves as a novel biomarker of hepatocellular carcinoma by mediating ferroptosis via regulating the arachidonic acid metabolism

OIT3 serves as a novel biomarker of hepatocellular carcinoma by mediating ferroptosis via regulating the arachidonic acid metabolism

Ferroptosis in Cancer Immunotherapy—Implications for Hepatocellular Carcinoma

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

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