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Chen F, Zhou Z, Fu J, Gao C. Selenomethionine Alleviates Alcohol-Induced Liver Injury by Inhibiting Ferroptosis. Dig Dis Sci 2025; 70:1779-1787. [PMID: 40029572 DOI: 10.1007/s10620-025-08960-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/24/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND AND AIM Selenomethionine (Se-Met) has been reported to reduce oxidative stress (OS) and hepatic injury; however, its role in alcoholic liver disease (ALD), particularly with ferroptosis, remains poorly understood. METHODS Oxidative stress was induced using ethanol, and ferroptosis was inhibited with ferrostatin-1 (fer-1) in L-02 and LX2 cell lines, respectively. The effects of Se-Met on alcohol-induced hepatocyte damage were evaluated in vitro by examining cell viability, lipid peroxidation, and the level of key ferroptosis-associated markers. In vivo, the interaction between Se-Met and ferroptosis was examined via an ALD mouse model through analyses of liver histology, lipid peroxidation, liver function, and ferroptosis-related indices. RESULTS In vitro and in vivo experiments indicated that both Se-Met and fer-1 have a significant protective role against alcohol-induced hepatocyte death and liver injury. Treatment with Se-Met or fer-1 can promote hepatocyte proliferation, ameliorate the typical symptoms of lipid peroxidation (e.g., glutathione depletion, superoxide dismutase enzyme activity, intracellular reactive oxygen species (ROS) level, malonaldehyde (MDA) content), and altered the expression of ferroptosis-related factors. Moreover, the findings indicated that the administration of Se-Met or fer-1 significantly ameliorated the pathological alterations and improved liver function indices associated with alcohol-induced liver damage in mice. These effects may collectively suppress the deleterious impact of ethanol on hepatic tissue. CONCLUSION This study concluded that the ferroptosis pathway regulated alcohol-induced hepatocyte injury. The administration of selenomethionine protects ALD by partially inhibiting the ferroptosis pathway, providing a novel therapeutic approach for ALD.
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Affiliation(s)
- Feng Chen
- Division of Gastroenterology, The Seventh Affiliated Hospital of Sun Yat-Sen University, No.628, Zhenyuan Road, Shenzhen, 518107, China.
| | - Zhenhua Zhou
- Department of Neurology, The Air Force Hospital of Southern Theater Command, PLA, Guangzhou, 510062, China
| | - Jinxian Fu
- Division of Infectious Diseases, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, China
| | - Chang Gao
- Division of Infectious Diseases, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, China
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Xu L, Zhao Y, Yang Y, Qi E, Liu B, Zhuang P, Song S, Chang T, Chen Z, Kang X, Xiong X. Constitutive Hepatic mTORC1 Activation Aggravates Alcohol-Induced Liver Injury via Endoplasmic Reticulum Stress-Mediated Ferroptosis. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00106-3. [PMID: 40204188 DOI: 10.1016/j.ajpath.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 03/04/2025] [Accepted: 03/21/2025] [Indexed: 04/11/2025]
Abstract
Alcohol-related liver disease (ALD), a consequence of excessive alcohol use, manifests across a broad spectrum of liver damage, ranging from steatosis to cirrhosis. DEPDC5 (DEP domain-containing protein 5) is a component of the GATOR1 (gap activity towards rags 1) complex, which functions as a repressor of the amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In this study, hepatocyte-specific Depdc5 knockout mice (Depdc5△Hep) were generated, and it was found that aberrant activation of mTORC1 caused by Depdc5 deletion led to exacerbated endoplasmic reticulum (ER) stress and hepatocyte ferroptosis in the livers of ethanol-fed mice. Torin-1, an ATP-competitive mTOR inhibitor, suppressed the mTORC1 activity and reversed the effects of Depdc5 deletion on ER stress and ferroptosis in ethanol-fed mouse livers. Furthermore, pharmacologic relief of ER stress using tauroursodeoxycholic acid or inhibition of ferroptosis with liproxstatin-1 both alleviated the liver abnormalities induced by Depdc5 ablation in ethanol-fed mice. In addition, the research uncovered that ER stress functions as an upstream signal of ferroptosis in the progression of ALD. These findings provide novel in vivo evidence that sustained mTORC1 activation leads to alcoholic liver injury by inducing ER stress and ferroptosis, suggesting that targeting these pathways may represent a potential therapeutic strategy for ALD.
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Affiliation(s)
- Lin Xu
- Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Key Laboratory of Metabolism and Integrative Physiology, School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, China; School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yuanyuan Zhao
- Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China; Department of Clinical Pharmacy, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Yang Yang
- Xinxiang Key Laboratory of Metabolism and Integrative Physiology, School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, China
| | - Enbo Qi
- Xinxiang Key Laboratory of Metabolism and Integrative Physiology, School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, China
| | - Boao Liu
- Xinxiang Key Laboratory of Metabolism and Integrative Physiology, School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, China
| | - Peili Zhuang
- Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Shiyi Song
- Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Tingmin Chang
- Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Zhiguo Chen
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Xiaohong Kang
- Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China; Department of Radiation Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
| | - Xiwen Xiong
- Henan Health Commission Key Laboratory of Gastrointestinal Cancer Prevention and Treatment, Department of Gastroenterology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China; Xinxiang Key Laboratory of Metabolism and Integrative Physiology, School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan, China; School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China.
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Xiong Z, Chen P, Wang Z, Yao L, Yuan M, Liu P, Sun M, Shu K, Jiang Y. Human umbilical cord-derived mesenchymal stem cells attenuate liver fibrosis by inhibiting hepatocyte ferroptosis through mitochondrial transfer. Free Radic Biol Med 2025; 231:163-177. [PMID: 40023296 DOI: 10.1016/j.freeradbiomed.2025.02.045] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
Liver fibrosis is a reversible dynamic pathological process induced by chronic liver injury. Without intervention, liver fibrosis can progress to become cirrhosis, liver failure, or hepatocellular carcinoma, thus posing a high global health burden. Therefore, effective therapies for liver fibrosis are urgently required. Although transplantation of mesenchymal stem cells (MSCs) has significant value as a treatment strategy for liver damage, the underlying mechanisms remain unclear. Chronic liver injury progression is significantly influenced by hepatocyte ferroptosis, and targeting ferroptosis is emerging as a potential treatment strategy for liver fibrosis. Here, we showed that the infusion of human umbilical cord-derived MSCs (hUC-MSCs) alleviated TAA-induced liver fibrosis, improved liver functionality, and decreased ferroptosis in mice. hUC-MSCs inhibit ferroptosis-related mitochondrial damage and lipid peroxidation in AML12 cells in vitro. Mechanistically, under oxidative stress, hUC-MSCs transfer healthy mitochondria to damaged hepatocytes through tunneling nanotubes (TNTs). Cytochalasin D (CytoD), an inhibitor of TNT formation, abrogated the protective effects of hUC-MSCs against ferroptosis. This research emphasizes the ability of hUC-MSCs to serve as a promising treatment for liver fibrosis via mitochondrial transfer through TNTs.
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Affiliation(s)
- Zhiyu Xiong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Ping Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Zheng Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Mengqin Yuan
- Department of Ultrasound Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430060, China.
| | - Pingji Liu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Muhua Sun
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Kan Shu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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Ma MJ, Lin J, Yang HJ, You J. Relationship between iron and lipid peroxidation in ferroptosis and effect of ferroptosis in metabolic dysfunction-associated steatotic liver disease. Shijie Huaren Xiaohua Zazhi 2025; 33:28-36. [DOI: 10.11569/wcjd.v33.i1.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/26/2024] [Accepted: 01/15/2025] [Indexed: 01/25/2025] Open
Abstract
The liver plays an irreplaceable role in human body functions, and liver damage of various causes is a major problem that plagues human health. China is a country with a heavy burden of hepatitis B, but in recent years, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has shown an increasing trend. Although the mechanism of liver injury caused by MASLD is not completely clear, it is inextricably related to the body's metabolism. MASLD is one of the most common chronic liver diseases and is considered to be a manifestation of metabolic syndrome in the liver. Ferroptosis is a cell death mechanism discovered in recent years, which is characterized by iron metabolism disorders and lipid peroxide accumulation. In recent years, several studies have found that there is an inextricable relationship between ferroptosis and liver disease. This article describes the relationship between iron or iron homeostasis and lipid peroxidation from the perspective of iron metabolism disorders, and the effect of ferroptosis in MASLD.
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Affiliation(s)
- Meng-Juan Ma
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jie Lin
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Hong-Ju Yang
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing You
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Ma MJ, Lin J, Yang HJ, You J. Relationship between iron and lipid peroxidation in ferroptosis and effect of ferroptosis in metabolic dysfunction-associated steatotic liver disease. Shijie Huaren Xiaohua Zazhi 2025; 33:34-42. [DOI: 10.11569/wcjd.v33.i1.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 12/26/2024] [Accepted: 01/15/2025] [Indexed: 01/22/2025] Open
Abstract
The liver plays an irreplaceable role in human body functions, and liver damage of various causes is a major problem that plagues human health. China is a country with a heavy burden of hepatitis B, but in recent years, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has shown an increasing trend. Although the mechanism of liver injury caused by MASLD is not completely clear, it is inextricably related to the body's metabolism. MASLD is one of the most common chronic liver diseases and is considered to be a manifestation of metabolic syndrome in the liver. Ferroptosis is a cell death mechanism discovered in recent years, which is characterized by iron metabolism disorders and lipid peroxide accumulation. In recent years, several studies have found that there is an inextricable relationship between ferroptosis and liver disease. This article describes the relationship between iron or iron homeostasis and lipid peroxidation from the perspective of iron metabolism disorders, and the effect of ferroptosis in MASLD.
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Affiliation(s)
- Meng-Juan Ma
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jie Lin
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Hong-Ju Yang
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Jing You
- Institute of Geriatric Medicine, Clinical Research Center for Geriatric Diseases, Department of Geriatric Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
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Liu X, Cai Y, Zhang Y, Zhang H, Tian S, Gong Y, Song Q, Chen X, Ma X, Wen Y, Chen Y, Zeng J. Artesunate: A potential drug for the prevention and treatment from hepatitis to hepatocellular carcinoma. Pharmacol Res 2024; 210:107526. [PMID: 39617278 DOI: 10.1016/j.phrs.2024.107526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/14/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
Liver cancer represents a multifactorial, multistage, and intricately progressive malignancy. Over the past decade, artesunate (ART), initially renowned for its anti-malarial efficacy, has been the focus of over 3000 studies uncovering its diverse pharmacological actions, including anti-inflammatory, immunoregulatory, metabolic regulatory, anti-fibrotic, and anti-cancer properties. This review highlights ART's role in the multistep progression from hepatitis to cancer and its underlying regulatory mechanisms, revealing signal transducer and activator of transcription 3 (STAT3) and ferroptosis (a novel form of programmed cell death) as promising therapeutic targets. ART demonstrates efficacy in inhibiting hepatitis virus infections, modulating inflammation, and facilitating recovery from inflammatory processes. During stages of hepatic fibrosis or cirrhosis, ART reverses fibrotic and cirrhotic changes by suppressing hepatic stellate cell activity, regulating inflammatory pathways, inhibiting hematopoietic stem cell proliferation, and inducing ferroptosis. Additionally, ART hinders hepatocellular carcinoma (HCC) cell proliferation, invasion, and metastasis, induces apoptosis and autophagy, combats drug resistance, and enhances chemosensitivity. Collectively, ART exhibits multi-step actions across multiple targets and signaling pathways, highlighting its potential as a clinical candidate for the prevention and treatment of liver cancer, from hepatitis and hepatic fibrosis to advanced HCC.
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Affiliation(s)
- Xinyue Liu
- School of Clinical Medicine, Chengdu University of Chinese Medicine, Chengdu 610075, China; Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Yilin Cai
- School of Clinical Medicine, Chengdu University of Chinese Medicine, Chengdu 610075, China; Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Yuanhao Zhang
- School of Clinical Medicine, Chengdu University of Chinese Medicine, Chengdu 610075, China
| | - Hetian Zhang
- School of Clinical Medicine, Chengdu University of Chinese Medicine, Chengdu 610075, China
| | - Sisi Tian
- School of Clinical Medicine, Chengdu University of Chinese Medicine, Chengdu 610075, China; Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Yuxia Gong
- School of Clinical Medicine, Chengdu University of Chinese Medicine, Chengdu 610075, China; Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Qinmei Song
- School of Clinical Medicine, Chengdu University of Chinese Medicine, Chengdu 610075, China; Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China
| | - Xiaotong Chen
- School of Clinical Medicine, Chengdu University of Chinese Medicine, Chengdu 610075, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yueqiang Wen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yu Chen
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
| | - Jinhao Zeng
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; Department of Gastroenterology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
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Qiu J, Le Y, Liu N, Chen L, Jiang Y, Wang Y, Fan X, Rong X, Yu Z, Li S, Dou X. Nuciferine Alleviates High-Fat Diet- and ApoE -/--Induced Hepatic Steatosis and Ferroptosis in NAFLD Mice via the PPARα Signaling Pathway. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:24417-24431. [PMID: 39445611 DOI: 10.1021/acs.jafc.4c04929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) causes significant global mortality and healthcare costs with no recommended pharmacological intervention for clinical management. Nuciferine (Nuc) is an alkaloid with aromatic rings, abundantly found in Nelumbo nucifera Gaertn. In this study, we explored the protective mechanisms of Nuc against hepatic steatosis and ferroptosis in NAFLD. High-fat diet (HFD) and healthy male ApoE-/- mice were used to induce NAFLD and a hypercholesterolemia model. Nuc was administered to the mice for four consecutive weeks from the ninth week. Various assessments, including histopathology, RNA sequencing, lipid metabolism, and ferroptosis-related protein expression, showed that Nuc alleviated hepatic steatosis and ferroptosis. We further showed that Nuc improves fatty acid accumulation and ferroptosis through the PPARα signaling pathway in mice and RSL3-treated AML-12 cells. The PPARα inhibitor GW6471 blocked Nuc's protective effects, leading to excess accumulation of iron ions. Thus, Nuc may be a potential therapeutic agent for NAFLD.
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Affiliation(s)
- Jiannan Qiu
- School of Life Science, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China
- School of Public Health, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China
| | - Yifei Le
- School of Life Science, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China
| | - Nian Liu
- School of Life Science, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China
| | - Lin Chen
- School of Life Science, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China
| | - Yuwei Jiang
- School of Life Science, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China
| | - Yuhao Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 268 Kaixuan Road, Shangcheng District, Hangzhou, Zhejiang 310020, China
| | - Xiaohui Fan
- Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, No. 38 Zheda Road, Hangzhou, Zhejiang 310027, China
| | - Xianglu Rong
- Chinese Medicine Institute, Guangdong Pharmaceutical University, No. 280 Outer Ring East Road, University Town, Guangzhou, Guangdong 510006, China
| | - Zhiling Yu
- Consun Chinese Medicines Research Centre for Renal Diseases, School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong 999077, China
| | - Songtao Li
- School of Public Health, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China
| | - Xiaobing Dou
- School of Life Science, Zhejiang Chinese Medical University, No. 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, China
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Li J, Feng R, Yang W, Liang P, Qiu T, Zhang J, Sun X, Li Q, Yang G, Yao X. Lysosomal iron accumulation and subsequent lysosomes-mitochondria iron transmission mediate PFOS-induced hepatocyte ferroptosis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 284:116890. [PMID: 39146593 DOI: 10.1016/j.ecoenv.2024.116890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 08/17/2024]
Abstract
Perfluorooctane sulfonate (PFOS) is known as a persistent organic pollutant. A significant correlation between PFOS and liver ferroptosis has been unveiled, but the precise mechanism needs to be elucidated. In prior research, we found that PFOS treatment provoked mitochondrial iron overload. In this study, we observed a gradual increase in lysosomal iron in L-O2 cells after exposure to PFOS for 0.5-24 h. In PFOS-exposed L-O2 cells, suppressing autophagy relieved the lysosomal iron overload. Inhibiting transient receptor potential mucolipin 1 (TRPML1), a calcium efflux channel on the lysosomal membrane, led to a further rise in lysosomal iron levels and decreased mitochondrial iron overload during PFOS treatment. Suppressing VDAC1, a subtype of voltage-dependent anion-selective channels (VDACs) on the outer mitochondrial membrane, had no impact on PFOS-triggered mitochondrial iron overload, whereas restraining VDAC2/3 relieved this condition. Although silencing VDAC2 relieved PFOS-induced mitochondrial iron overload, it had no effect on PFOS-triggered lysosomal iron overload. Silencing VDAC3 alleviated PFOS-mediated mitochondrial iron overload and led to an additional increase in lysosomal iron. Therefore, we regarded VDAC3 as the specific VDACs subtype that mediated the lysosomes-mitochondria iron transfer. Additionally, in the presence of PFOS, an enhanced association between TRPML1 and VDAC3 was found in mice liver tissue and L-O2 cells. Our research unveils a novel regulatory mechanism of autophagy on the iron homeostasis and the effect of TRPML1-VDAC3 interaction on lysosomes-mitochondria iron transfer, giving an explanation of PFOS-induced ferroptosis and shedding some light on the role of classic calcium channels in iron transmission.
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Affiliation(s)
- Jixun Li
- Environment and Occupation Health Department, Dalian Medical University, 9 Lushun South Road, Dalian, China
| | - Ruzhen Feng
- Environment and Occupation Health Department, Dalian Medical University, 9 Lushun South Road, Dalian, China
| | - Wei Yang
- Environment and Occupation Health Department, Dalian Medical University, 9 Lushun South Road, Dalian, China
| | - Peiyao Liang
- Environment and Occupation Health Department, Dalian Medical University, 9 Lushun South Road, Dalian, China
| | - Tianming Qiu
- Environment and Occupation Health Department, Dalian Medical University, 9 Lushun South Road, Dalian, China
| | - Jingyuan Zhang
- Environment and Occupation Health Department, Dalian Medical University, 9 Lushun South Road, Dalian, China
| | - Xiance Sun
- Environment and Occupation Health Department, Dalian Medical University, 9 Lushun South Road, Dalian, China
| | - Qiujuan Li
- Nutrition and Food Safety Department, Dalian Medical University, 9 Lushun South Road, Dalian, China
| | - Guang Yang
- Nutrition and Food Safety Department, Dalian Medical University, 9 Lushun South Road, Dalian, China
| | - Xiaofeng Yao
- Environment and Occupation Health Department, Dalian Medical University, 9 Lushun South Road, Dalian, China.
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Jiang Y, Hui D, Pan Z, Yu Y, Liu L, Yu X, Wu C, Sun M. Curcumin promotes ferroptosis in hepatocellular carcinoma via upregulation of ACSL4. J Cancer Res Clin Oncol 2024; 150:429. [PMID: 39311951 PMCID: PMC11420324 DOI: 10.1007/s00432-024-05878-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 07/01/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND Ferroptosis, a novel iron-ion-dependent metabolic cell death mode with lipid peroxides as the main driving substrate, plays an irreplaceable role in the development and preventive treatment of hepatocellular carcinoma. Curcumin has potent pharmacological anti-tumor effects. AIM OF THE STUDY We aimed to evaluate the ex vivo and in vivo cancer inhibitory activity of curcumin and its specific mechanism of action. MATERIALS AND METHODS We used the hepatocellular carcinoma cell lines HepG2 and SMMC7721 to assess the direct inhibition of hepatocellular carcinoma proliferation by curcumin in vitro and a tumor xenograft model to evaluate the in vivo cancer inhibitory effect of curcumin. RESULTS In this study, we found that ferroptosis's inhibitors specifically reversed the curcumin-induced cell death pattern in HCC. After curcumin intervention, there was a substantial increase in MDA levels and iron ion levels, and a decrease in intracellular GSH levels. Meanwhile, the expression of GPX4 and SLC7A11 was significantly reduced at the protein levels, while ACSL4 and PTGS2 expression was significantly increased. CONCLUSIONS This study showed that curcumin significantly decreased the proliferation of HCC cells and significantly increased the sensitivity of ferroptosis. These results suggest that ACSL4 is a viable target for curcumin-induced ferroptosis in treating HCC.
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Affiliation(s)
- Yulang Jiang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China
| | - Dengcheng Hui
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China
| | - Ziyang Pan
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China
| | - Yongxin Yu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China
| | - Lu Liu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China
| | - Xiaofan Yu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China
| | - Chao Wu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China
| | - Mingyu Sun
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No.528 Zhangheng Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China.
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10
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Zhou Y, Pang N, Li W, Li Q, Luo J, Gu Y, Hu Q, Ding YJ, Sun Y, Pan J, Gao M, Xiao Y, Ma S, Hao Y, Xing H, Fang EF, Ling W, Zhang Z, Yang L. Inhibition of ethanol-induced eNAMPT secretion attenuates liver ferroptosis through BAT-Liver communication. Redox Biol 2024; 75:103274. [PMID: 39059204 PMCID: PMC11327441 DOI: 10.1016/j.redox.2024.103274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/15/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND & AIMS Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) has long been recognized as an adipokine. However, the exact role of eNAMPT in alcoholic liver disease (ALD) and its relevance to brown adipose tissue (BAT) remain largely unknown. This study aimed to evaluate the impact of eNAMPT on liver function and the underlying mechanisms involved in BAT-Liver communication. METHODS Serum eNAMPT levels were detected in the serum of both ALD patients and mice. Chronic and binge ethanol feeding was used to induce alcoholic liver injury in mice. An eNAMPT antibody, a coculture model of brown adipocytes and hepatocytes, and BAT-specific Nampt knockdown mice were used to investigate the role of eNAMPT in ALD. RESULTS Serum eNAMPT levels are elevated in ALD patients and are significantly positively correlated with the liver injury index. In ALD mice, neutralizing eNAMPT reduced the elevated levels of circulating eNAMPT induced by ethanol and attenuated liver injury. In vitro experiments revealed that eNAMPT induced hepatocyte ferroptosis through the TLR4-dependent mitochondrial ROS-induced ferritinophagy pathway. Furthermore, ethanol stimulated eNAMPT secretion from brown adipocytes but not from other adipocytes. In the coculture model, ethanol-induced release of eNAMPT from brown adipocytes promoted hepatocyte ferroptosis. In BAT-specific Nampt-knockdown mice, ethanol-induced eNAMPT secretion was significantly reduced, and alcoholic liver injury were attenuated. These effects can be reversed by intraperitoneal injection of eNAMPT. CONCLUSION Inhibition of ethanol-induced eNAMPT secretion from BAT attenuates liver injury and ferroptosis. Our study reveals a previously uncharacterized critical role of eNAMPT-mediated BAT-Liver communication in ALD and highlights its potential as a therapeutic target.
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Affiliation(s)
- Yujia Zhou
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Nengzhi Pang
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenli Li
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Immunization Programs, Guangzhou Huadu District Center for Disease Control and Prevention, Guangzhou, Guangdong, China
| | - Qiuyan Li
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jing Luo
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yingying Gu
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qianrong Hu
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Women Health Care, Guangzhou Baiyun District Maternal and Child Health Hospital, Guangzhou, Guangdong, China
| | - Yi Jie Ding
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yan Sun
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jie Pan
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Mengqi Gao
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ying Xiao
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Sixi Ma
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yanxu Hao
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Huichun Xing
- Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, Beijing, China; Peking University Ditan Teaching Hospital, Beijing, China
| | - Evendro Fei Fang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478, Lørenskog, Norway
| | - Wenhua Ling
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhenfeng Zhang
- Department of Radiology, Translational Medicine Center and Guangdong Provincial Education Department, Key Laboratory of Nano-Immunoregulation Tumor Microenvironment, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Lili Yang
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China.
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11
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Jiang M, Wu S, Xie K, Zhou G, Zhou W, Bao P. The significance of ferroptosis in renal diseases and its therapeutic potential. Heliyon 2024; 10:e35882. [PMID: 39220983 PMCID: PMC11363859 DOI: 10.1016/j.heliyon.2024.e35882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 04/04/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
Kidney diseases are significant global public health concern, with increasing prevalence and substantial economic impact. Developing novel therapeutic approaches are essential for delaying disease progression and improving patient quality of life. Cell death signifying the termination of cellular life, could facilitate appropriate bodily development and internal homeostasis. Recently, regulated cell death (RCD) forms such as ferroptosis, characterized by iron-dependent lipid peroxidation, has garnered attention in diverse renal diseases and other pathological conditions. This review offers a comprehensive examination of ferroptosis, encompassing an analysis of the involvement of iron and lipid metabolism, the System Xc - /glutathione/glutathione peroxidase 4 signaling, and additional associated pathways. Meanwhile, the review delves into the potential of targeting ferroptosis as a therapeutic approach in the management of acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy, and renal tumors. Furthermore, it emphasizes the significance of ferroptosis in the transition from AKI to CKD and further accentuates the potential for repurposing drug and utilizing traditional medicine in targeting ferroptosis-related pathways for clinical applications. The integrated review provides valuable insights into the role of ferroptosis in kidney diseases and highlights the potential for targeting ferroptosis as a therapeutic strategy.
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Affiliation(s)
- Mingzhu Jiang
- The Yangzhou Clinical Medical College of Xuzhou Medical University, Yangzhou, China
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Shujun Wu
- The Yangzhou School of Clinical Medicine of Dalian Medical University, Yangzhou, China
| | - Kun Xie
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Gang Zhou
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
| | - Wei Zhou
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children's Regional Medical Center, Hangzhou, China
| | - Ping Bao
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China
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12
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Jiang Y, Yu Y, Pan Z, Wang Z, Sun M. Ginsenoside RK1 Induces Ferroptosis in Hepatocellular Carcinoma Cells through an FSP1-Dependent Pathway. Pharmaceuticals (Basel) 2024; 17:871. [PMID: 39065721 PMCID: PMC11279434 DOI: 10.3390/ph17070871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), currently ranking as the third most lethal malignancy, poses a grave threat to human health. Ferroptosis, a form of programmed cell demise, has emerged as a promising therapeutic target in HCC treatment. In this study, we investigated the impact of ginsenoside RK1 on ferroptosis induction in HCC cells and elucidated the underlying mechanisms. METHODS The HCC cell line HepG2 was utilized to evaluate the effects of ginsenoside RK1. Distinct dosages of ginsenoside RK1 (25 μM, 50 μM, and 100 μM) were selected based on half-maximal inhibitory concentration (IC50) values. Cellular viability was assessed using a CCK8 assay, cytotoxicity was measured via lactate dehydrogenase (LDH) release assay, and colony-forming ability was evaluated using the clone formation assay. Various inhibitors targeting apoptosis (Z-VAD-FMK 20 μM), necrosis (Nec-1, 10 μM), and ferroptosis (Fer-1, 10 μM; Lip-1, 1 μM) were employed to assess ginsenoside RK1's impact on cell demise. Intracellular levels of key ions, including glutathione (GSH), malondialdehyde (MDA), and iron ions, were quantified, and the protein expression levels of ferroptosis-related genes were evaluated. The sensitivity of HCC cells to ferroptosis induction by ginsenoside RK1 was examined following the overexpression and silencing of the aforementioned target genes. RESULTS Ginsenoside RK1 exhibited an inhibitory effect on HCC cells with an IC50 value of approximately 20 μM. It attenuated cellular viability and colony-forming capacity in a dose-dependent manner, concurrently reducing intracellular GSH levels and increasing intracellular Malondialdehyde (MDA) and iron ion contents. Importantly, cell demise induced by ginsenoside RK1 was specifically counteracted by ferroptosis inhibitors. Furthermore, the modulation of Ferroptosis suppressor protein 1 (FSP1) expression influenced the ability of ginsenoside RK1 to induce ferroptosis. FSP1 overexpression or silencing enhanced or inhibited ferroptosis induction by ginsenoside RK1, respectively. CONCLUSIONS Ginsenoside RK1 enhances ferroptosis in hepatocellular carcinoma through an FSP1-dependent pathway.
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Affiliation(s)
- Yulang Jiang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (Y.Y.); (Z.P.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yongxin Yu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (Y.Y.); (Z.P.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ziyang Pan
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (Y.Y.); (Z.P.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ziyuan Wang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (Y.Y.); (Z.P.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mingyu Sun
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Y.J.); (Y.Y.); (Z.P.)
- Internal Medicine in Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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13
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Shu YJ, Lao B, Qiu YY. Research progress of ferroptosis regulating lipid peroxidation and metabolism in occurrence and development of primary liver cancer. World J Gastrointest Oncol 2024; 16:2335-2349. [PMID: 38994128 PMCID: PMC11236230 DOI: 10.4251/wjgo.v16.i6.2335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/06/2024] [Accepted: 04/11/2024] [Indexed: 06/13/2024] Open
Abstract
As a highly aggressive tumor, the pathophysiological mechanism of primary liver cancer has attracted much attention. In recent years, factors such as ferroptosis regulation, lipid peroxidation and metabolic abnormalities have emerged in the study of liver cancer, providing a new perspective for understanding the development of liver cancer. Ferroptosis regulation, lipid peroxidation and metabolic abnormalities play important roles in the occurrence and development of liver cancer. The regulation of ferroptosis is involved in apoptosis and necrosis, affecting cell survival and death. Lipid peroxidation promotes oxidative damage and promotes the invasion of liver cancer cells. Metabolic abnormalities, especially the disorders of glucose and lipid metabolism, directly affect the proliferation and growth of liver cancer cells. Studies of ferroptosis regulation and lipid peroxidation may help to discover new therapeutic targets and improve therapeutic outcomes. The understanding of metabolic abnormalities can provide new ideas for the prevention of liver cancer, and reduce the risk of disease by adjusting the metabolic process. This review focuses on the key roles of ferroptosis regulation, lipid peroxidation and metabolic abnormalities in this process.
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Affiliation(s)
- Yu-Jie Shu
- Department of Gastroenterology, Yinzhou District Second Hospital, Ningbo 315199, Zhejiang Province, China
| | - Bo Lao
- Department of Gastroenterology, Yinzhou District Second Hospital, Ningbo 315199, Zhejiang Province, China
| | - Ying-Yang Qiu
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
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14
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Lin L, Li X, Li Y, Lang Z, Li Y, Zheng J. Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis. J Pharm Anal 2024; 14:100902. [PMID: 38784156 PMCID: PMC11112007 DOI: 10.1016/j.jpha.2023.11.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/02/2023] [Accepted: 11/21/2023] [Indexed: 05/25/2024] Open
Abstract
Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), a process associated with ferroptosis. Ginsenoside Rb1 (GRb1), a major active component extracted from Panax ginseng, inhibits HSC activation. However, the potential role of GRb1 in mediating HSC ferroptosis remains unclear. This study examined the effect of GRb1 on liver fibrosis both in vivo and in vitro, using CCl4-induced liver fibrosis mouse model and primary HSCs, LX-2 cells. The findings revealed that GRb1 effectively inactivated HSCs in vitro, reducing alpha-smooth muscle actin (α-SMA) and Type I collagen (Col1A1) levels. Moreover, GRb1 significantly alleviated CCl4-induced liver fibrosis in vivo. From a mechanistic standpoint, the ferroptosis pathway appeared to be central to the antifibrotic effects of GRb1. Specifically, GRb1 promoted HSC ferroptosis both in vivo and in vitro, characterized by increased glutathione depletion, malondialdehyde production, iron overload, and accumulation of reactive oxygen species (ROS). Intriguingly, GRb1 increased Beclin 1 (BECN1) levels and decreased the System Xc-key subunit SLC7A11. Further experiments showed that BECN1 silencing inhibited GRb1-induced effects on HSC ferroptosis and mitigated the reduction of SLC7A11 caused by GRb1. Moreover, BECN1 could directly interact with SLC7A11, initiating HSC ferroptosis. In conclusion, the suppression of BECN1 counteracted the effects of GRb1 on HSC inactivation both in vivo and in vitro. Overall, this study highlights the novel role of GRb1 in inducing HSC ferroptosis and promoting HSC inactivation, at least partly through its modulation of BECN1 and SLC7A11.
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Affiliation(s)
- Lifan Lin
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Xinmiao Li
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yifei Li
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Zhichao Lang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yeping Li
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Jianjian Zheng
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
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15
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Huang C, Jiang Y, Bao Q, Wang L, Tang L, Liu Y, Yang L. Study on the differential hepatotoxicity of raw polygonum multiflorum and polygonum multiflorum praeparata and its mechanism. BMC Complement Med Ther 2024; 24:161. [PMID: 38632548 PMCID: PMC11022370 DOI: 10.1186/s12906-024-04463-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 03/31/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Polygonum multiflorum (PM), a widely used traditional Chinese medicine herb, is divided into two forms, namely raw polygonum multiflorum (RPM) and polygonum multiflorum praeparata (PMP), according to the processing procedure. Emerging data has revealed the differential hepatotoxicity of RPM and PMP, however, its potential mechanism is still unclear. METHODS In our study, we investigated the differential hepatotoxicity of RPM and PMP exerted in C57BL/6 mice. First, sera were collected for biochemical analysis and HE staining was applied to examine the morphological alternation of the liver. Then we treated L02 cells with 5 mg / mL of RPM or PMP. The CCK8 and EdU assays were utilized to observe the viability and proliferation of L02 cells. RNA sequencing was performed to explore the expression profile of L02 cells. Western blotting was performed to detect the expression level of ferroptosis-related protein. Flow cytometry was used to evaluate ROS accumulation. RESULTS In our study, a significant elevation in serum ALT, AST and TBIL levels was investigated in the RMP group, while no significant differences were observed in the PMP group, compared to that of the CON group. HE staining showed punctate necrosis, inflammatory cell infiltration and structural destruction can be observed in the RPM group, which can be significantly attenuated after processing. In addition, we also found RPM could decrease the viability and proliferation capacity of L02 cells, which can be reversed by ferroptosis inhibitor. RNA sequencing data revealed the adverse effect of PM exerted on the liver is closely associated with ferroptosis. Western blotting assay uncovered the protein level of GPX4, HO-1 and FTL was sharply decreased, while the ROS content was dramatically elevated in L02 cells treated with RPM, which can be partially restored after processing. CONCLUSIONS The hepatotoxicity induced by RPM was significantly lower than the PMP, and its potential mechanism is associated with ferroptosis.
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Affiliation(s)
- Chaowen Huang
- Department of Preparations, the First Hospital of Hunan University of Chinese Medicine, Changsha City, China
- Institute of Emergency Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, 69 Jiefang Western Road, Changsha City, 410000, Hunan, China
| | - Yu Jiang
- Institute of Emergency Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, 69 Jiefang Western Road, Changsha City, 410000, Hunan, China
| | - Qing Bao
- Department of Preparations, the First Hospital of Hunan University of Chinese Medicine, Changsha City, China
| | - Lu Wang
- Department of Preparations, the First Hospital of Hunan University of Chinese Medicine, Changsha City, China
| | - Lin Tang
- Department of Preparations, the First Hospital of Hunan University of Chinese Medicine, Changsha City, China
| | - Yanjuan Liu
- Institute of Emergency Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, 69 Jiefang Western Road, Changsha City, 410000, Hunan, China.
| | - Lei Yang
- Department of Preparations, the First Hospital of Hunan University of Chinese Medicine, Changsha City, China.
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Yu T, Lu X, Liang Y, Yang L, Yin Y, Chen H. Naringenin alleviates liver fibrosis by triggering autophagy-dependent ferroptosis in hepatic stellate cells. Heliyon 2024; 10:e28865. [PMID: 38576562 PMCID: PMC10990976 DOI: 10.1016/j.heliyon.2024.e28865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 03/26/2024] [Accepted: 03/26/2024] [Indexed: 04/06/2024] Open
Abstract
Inhibition of activated hepatic stellate cells (HSCs) is a promising approach for treating liver fibrosis, and the ferroptosis has emerged as a pivotal mechanism to achieve this inhibition. The effects of naringenin, a flavonoid with anti-inflammatory properties, have not been thoroughly examined in liver fibrosis. Therefore, we used cholestasis model to study the effect of naringenin on liver fibrosis. Our findings demonstrated a significant exacerbation of liver tissue damage and fibrosis in mice subjected to bile duct ligation (BDL), accompanied by a substantial upregulation of fibrogenesis-related gene expression. Notably, naringenin administration markedly alleviated liver injury and fibrosis in these mice. Furthermore, naringenin exhibited inhibitory effects on the activation of HSCs, concurrently inducing ferroptosis. Importantly, naringenin significantly increased autophagic activity in HSCs. This effect was counteracted by co-administration of the autophagy inhibitor 3-MA, leading to a notable reduction in naringenin-induced HSC ferroptosis. In BDL model mice, naringenin demonstrated a mitigating effect on liver fibrosis, suggesting a potential correlation with naringenin-induced ferroptosis of HSCs. These results provide novel insights into the molecular mechanisms of naringenin-induced ferroptosis and highlight autophagy-dependent ferroptosis as a promising therapeutic strategy for liver fibrosis.
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Affiliation(s)
- Ting Yu
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Xuejia Lu
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Yan Liang
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Lin Yang
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Yuehan Yin
- China HuaYou Group Corporation, Beijing, 100724, People's Republic of China
| | - Hong Chen
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
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17
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Wang N, Que H, Luo Q, Zheng W, Li H, Wang Q, Gu J. Mechanisms of ferroptosis in nonalcoholic fatty liver disease and therapeutic effects of traditional Chinese medicine: a review. Front Med (Lausanne) 2024; 11:1356225. [PMID: 38590315 PMCID: PMC10999571 DOI: 10.3389/fmed.2024.1356225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/22/2024] [Indexed: 04/10/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)), and lobular inflammation and hepatocyte damage (which characterize nonalcoholic steatohepatitis (NASH) are found in most patients). A subset of patients will gradually develop liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma, which is a deadly disease that threatens human life worldwide. Ferroptosis, a novel nonapoptotic form of programmed cell death (PCD) characterized by iron-dependent accumulation of reactive oxygen radicals and lipid peroxides, is closely related to NAFLD. Traditional Chinese medicine (TCM) has unique advantages in the prevention and treatment of NAFLD due to its multicomponent, multipathway and multitarget characteristics. In this review, we discuss the effect of TCM on NAFLD by regulating ferroptosis, in order to provide reference for the further development and application of therapeutic drugs to treat NAFLD.
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Affiliation(s)
- Nan Wang
- College of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Hanyun Que
- College of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Qiulin Luo
- College of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Wenxin Zheng
- College of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Hong Li
- College of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Qin Wang
- College of Pharmacy, Southwest Minzu University, Chengdu, China
- BMI Center for Biomass Materials and Nanointerfaces, College of Biomass Science and Engineering, Sichuan University, Chengdu, China
| | - Jian Gu
- College of Pharmacy, Southwest Minzu University, Chengdu, China
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18
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Jiang Y, Yu Y, Pan Z, Glandorff C, Sun M. Ferroptosis: a new hunter of hepatocellular carcinoma. Cell Death Discov 2024; 10:136. [PMID: 38480712 PMCID: PMC10937674 DOI: 10.1038/s41420-024-01863-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 02/06/2024] [Accepted: 02/12/2024] [Indexed: 03/17/2024] Open
Abstract
Ferroptosis is an iron ion-dependent, regulatory cell death modality driven by intracellular lipid peroxidation that plays a key role in the development of HCC. Studies have shown that various clinical agents (e.g., sorafenib) have ferroptosis inducer-like effects and can exert therapeutic effects by modulating different key factors in the ferroptosis pathway. This implies that targeting tumor cell ferroptosis may be a very promising strategy for tumor therapy. In this paper, we summarize the prerequisites and defense systems for the occurrence of ferroptosis and the regulatory targets of drug-mediated ferroptosis action in HCC, the differences and connections between ferroptosis and other programmed cell deaths. We aim to summarize the theoretical basis, classical inducers of ferroptosis and research progress of ferroptosis in HCC cells, clued to the treatment of HCC by regulating ferroptosis network. Further investigation of the specific mechanisms of ferroptosis and the development of hepatocellular carcinoma and interventions at different stages of hepatocellular carcinoma will help us to deepen our understanding of hepatocellular carcinoma, with a view to providing new and more precise preventive as well as therapeutic measures for patients.
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Affiliation(s)
- Yulang Jiang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yongxin Yu
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ziyang Pan
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Christian Glandorff
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- University Clinic of Hamburg at the HanseMerkur Center of TCM, Hamburg, Germany
| | - Mingyu Sun
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Key Laboratory of Liver and Kidney Diseases, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Yamada N, Karasawa T, Ito J, Yamamuro D, Morimoto K, Nakamura T, Komada T, Baatarjav C, Saimoto Y, Jinnouchi Y, Watanabe K, Miura K, Yahagi N, Nakagawa K, Matsumura T, Yamada KI, Ishibashi S, Sata N, Conrad M, Takahashi M. Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis. Nat Commun 2024; 15:2195. [PMID: 38472233 DOI: 10.1038/s41467-024-46386-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.
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Affiliation(s)
- Naoya Yamada
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
- Division of Gastroenterological, General and Transplant Surgery, Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan.
- Institute of Metabolism and Cell Death, Molecular Target and Therapeutics Center, Helmholtz Munich, Neuherberg, Bavaria, Germany.
| | - Tadayoshi Karasawa
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
| | - Junya Ito
- Laboratory of Food Function Analysis, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Daisuke Yamamuro
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Kazushi Morimoto
- Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
| | - Toshitaka Nakamura
- Institute of Metabolism and Cell Death, Molecular Target and Therapeutics Center, Helmholtz Munich, Neuherberg, Bavaria, Germany
| | - Takanori Komada
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Chintogtokh Baatarjav
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Yuma Saimoto
- Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
| | - Yuka Jinnouchi
- Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
| | - Kazuhisa Watanabe
- Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Kouichi Miura
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Naoya Yahagi
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Kiyotaka Nakagawa
- Laboratory of Food Function Analysis, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan
| | - Takayoshi Matsumura
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
- Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Ken-Ichi Yamada
- Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
| | - Shun Ishibashi
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Naohiro Sata
- Division of Gastroenterological, General and Transplant Surgery, Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Marcus Conrad
- Institute of Metabolism and Cell Death, Molecular Target and Therapeutics Center, Helmholtz Munich, Neuherberg, Bavaria, Germany
| | - Masafumi Takahashi
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
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20
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Mo JQ, Zhang SY, Li Q, Chen MX, Zheng YQ, Xie X, Zhang R, Wang SS. Immunomodulation of cuproptosis and ferroptosis in liver cancer. Cancer Cell Int 2024; 24:22. [PMID: 38200525 PMCID: PMC10777659 DOI: 10.1186/s12935-023-03207-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 12/30/2023] [Indexed: 01/12/2024] Open
Abstract
According to statistics, the incidence of liver cancer is increasing yearly, and effective treatment of liver cancer is imminent. For early liver cancer, resection surgery is currently the most effective treatment. However, resection does not treat the disease in advanced patients, so finding a method with a better prognosis is necessary. In recent years, ferroptosis and cuproptosis have been gradually defined, and related studies have proved that they show excellent results in the therapy of liver cancer. Cuproptosis is a new form of cell death, and the use of cuproptosis combined with ferroptosis to inhibit the production of hepatocellular carcinoma cells has good development prospects and is worthy of in-depth discussion by researchers. In this review, we summarize the research progress on cuproptosis combined with ferroptosis in treating liver cancer, analyze the value of cuproptosis and ferroptosis in the immune of liver cancer, and propose potential pathways in oncotherapy with the combination of cuproptosis and ferroptosis, which can provide background knowledge for subsequent related research.
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Affiliation(s)
- Jia-Qian Mo
- School of Life Sciences and Biopharmaceutics, Guang Dong Pharmaceutical University, Guangzhou, 51006, China
| | - Shen-Yan Zhang
- School of Life Sciences and Biopharmaceutics, Guang Dong Pharmaceutical University, Guangzhou, 51006, China
| | - Qiang Li
- School of Life Sciences and Biopharmaceutics, Guang Dong Pharmaceutical University, Guangzhou, 51006, China
| | - Mo-Xian Chen
- State Key Laboratory of Tree Genetics and Breeding, Co-Innovation Center for Sustainable Forestry in Southern China and College of Life Sciences, Nanjing Forestry University, Nanjing, 210037, China
| | - Yue-Qing Zheng
- Guang Zhou Zengcheng District Centre for Disease Control and Prevention, Guang Dong, 511300, China
| | - Xin Xie
- School of Life and Environmental Sciences, Shaoxing University, Shaoxing, 312000, Zhejiang, China
| | - Rongxin Zhang
- School of Life Sciences and Biopharmaceutics, Guang Dong Pharmaceutical University, Guangzhou, 51006, China.
| | - Shan-Shan Wang
- School of Life Sciences and Biopharmaceutics, Guang Dong Pharmaceutical University, Guangzhou, 51006, China.
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21
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Pourhanifeh MH, Hosseinzadeh A, Koosha F, Reiter RJ, Mehrzadi S. Therapeutic Effects of Melatonin in the Regulation of Ferroptosis: A Review of Current Evidence. Curr Drug Targets 2024; 25:543-557. [PMID: 38706348 DOI: 10.2174/0113894501284110240426074746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/12/2024] [Accepted: 03/18/2024] [Indexed: 05/07/2024]
Abstract
Ferroptosis is implicated in the pathogenesis of multiple diseases, including neurodegenerative diseases, cardiovascular diseases, kidney pathologies, ischemia-reperfusion injury, and cancer. The current review article highlights the involvement of ferroptosis in traumatic brain injury, acute kidney damage, ethanol-induced liver injury, and PM2.5-induced lung injury. Melatonin, a molecule produced by the pineal gland and many other organs, is well known for its anti- aging, anti-inflammatory, and anticancer properties and is used in the treatment of different diseases. Melatonin's ability to activate anti-ferroptosis pathways including sirtuin (SIRT)6/p- nuclear factor erythroid 2-related factor 2 (Nrf2), Nrf2/ antioxidant responsive element (ARE)/ heme oxygenase (HO-1)/SLC7A11/glutathione peroxidase (GPX4)/ prostaglandin-endoperoxide synthase 2 (PTGS2), extracellular signal-regulated kinase (ERK)/Nrf2, ferroportin (FPN), Hippo/ Yes-associated protein (YAP), Phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) and SIRT6/ nuclear receptor coactivator 4 (NCOA4)/ ferritin heavy chain 1 (FTH1) signaling pathways suggests that it could serve as a valuable therapeutic agent for preventing cell death associated with ferroptosis in various diseases. Further research is needed to fully understand the precise mechanisms by which melatonin regulates ferroptosis and its potential as a therapeutic target.
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Affiliation(s)
- Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fereshteh Koosha
- Department of Radiology Technology, Faculty of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cellular & Structural Biology, University of Texas, Health Science Center, San Antonio, USA
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
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22
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Zheng Y, Wang L, Wang J, Zhao T, Wang J. Modulation of the HIF-1α-NCOA4-FTH1 Signaling Axis Regulating Ferroptosis-induced Hepatic Stellate Cell Senescence to Explore the Anti-hepatic Fibrosis Mechanism of Curcumol. Curr Med Chem 2024; 31:2821-2837. [PMID: 38351696 DOI: 10.2174/0109298673271261231213051410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/08/2023] [Accepted: 11/23/2023] [Indexed: 06/05/2024]
Abstract
INTRODUCTION Senescence of activated hepatic stellate cells (HSC) reduces extracellular matrix expression to reverse liver fibrosis. Ferroptosis is closely related to cellular senescence, but its regulatory mechanisms need to be further investigated. The iron ions weakly bound to ferritin in the cell are called labile iron pool (LIP), and together with ferritin, they maintain cellular iron homeostasis and regulate the cell's sensitivity to ferroptosis. METHODS We used lipopolysaccharide (LPS) to construct a pathological model group and divided the hepatic stellate cells into a blank group, a model group, and a curcumol 12.5 mg/L group, a curcumol 25 mg/L group, and a curcumol 50 mg/L group. HIF-1α-NCOA4- FTH1 signalling axis, ferroptosis and cellular senescence were detected by various cellular molecular biology experiments. RESULT We found that curcumol could induce hepatic stellate cell senescence by promoting iron death in hepatic stellate cells. Curcumol induced massive deposition of iron ions in hepatic stellate cells by activating the HIF-1α-NCOA4-FTH1 signalling axis, which further led to iron overload and lipid peroxidation-induced ferroptosis. Interestingly, our knockdown of HIF-1α rescued curcumol-induced LIP and iron deposition in hepatic stellate cells, suggesting that HIF-1α is a key target of curcumol in regulating iron metabolism and ferroptosis. We were able to rescue curcumol-induced hepatic stellate cell senescence when we reduced LIP and iron ion deposition using iron chelators. CONCLUSION Overall, curcumol induces ferroptosis and cellular senescence by increasing HIF-1α expression and increasing NCOA4 interaction with FTH1, leading to massive deposition of LIP and iron ions, which may be the molecular biological mechanism of its anti-liver fibrosis.
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Affiliation(s)
- Yang Zheng
- Department of Medicine, Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, 530222, Guangxi , China
| | - Lei Wang
- Department of Medicine, Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, 530222, Guangxi , China
| | - Jiaru Wang
- Department of Physiology, College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, 530222, Guangxi , China
| | - Tiejian Zhao
- Department of Physiology, College of Basic Medicine, Guangxi University of Chinese Medicine, Nanning, 530222, Guangxi , China
| | - Jiahui Wang
- Department of Medicine, Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning, 530222, Guangxi , China
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23
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Wang Z, Zhou C, Zhang Y, Tian X, Wang H, Wu J, Jiang S. From synergy to resistance: Navigating the complex relationship between sorafenib and ferroptosis in hepatocellular carcinoma. Biomed Pharmacother 2024; 170:116074. [PMID: 38147732 DOI: 10.1016/j.biopha.2023.116074] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 12/17/2023] [Accepted: 12/21/2023] [Indexed: 12/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a major global health burden, and sorafenib, a multi-kinase inhibitor, has shown effectiveness in the treatment of HCC and is considered as the first-line therapy for advanced HCC. However, the response to sorafenib varies among patients, and the development of drug resistance poses a prevalent obstacle. Ferroptosis, a newly characterized form of cell death featured by iron-dependent lipid peroxidation, has emerged as a critical player in the reaction to sorafenib therapy in HCC. The induction of ferroptosis has been shown to augment the anticancer benefits of sorafenib. However, it has also been observed to contribute to sorafenib resistance. This review presents a comprehensive and thorough analysis that elucidates the intricate relationship between ferroptosis and sorafenib over recent years, aiming to formulate effective therapeutic approaches for liver cancer. Based on this exploration, we propose innovative strategies intended to overcome sorafenib resistance via targeted modulation of ferroptosis.
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Affiliation(s)
- Zijian Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chunyang Zhou
- Department of Radiation Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Yiming Zhang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Xinchen Tian
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Haochen Wang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China
| | - Jibiao Wu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining First People's Hospital, Shandong First Medical University, Jining, Shandong, China; College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
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24
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Cai M, Luo J, Yang C, Yang X, Zhang C, Ma L, Cheng Y. ABHD12 contributes to tumorigenesis and sorafenib resistance by preventing ferroptosis in hepatocellular carcinoma. iScience 2023; 26:108340. [PMID: 38053637 PMCID: PMC10694648 DOI: 10.1016/j.isci.2023.108340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 10/05/2023] [Accepted: 10/23/2023] [Indexed: 12/07/2023] Open
Abstract
Sorafenib induces ferroptosis, making it a useful treatment against advanced liver hepatocellular carcinoma (LIHC). However, sorafenib resistance is extremely common among LIHC patients. Here, we used a comprehensive approach to investigate the effects of ABHD12, which regulates tumorigenesis and sorafenib resistance in LIHC. We validated ABHD12 expression was upregulated in LIHC tissue, which correlated with worse overall survival and related to tumor size or stage. ABHD12 facilitated a pro-tumorigenic phenotype involving increased cell proliferation, migration, and clonogenicity as well as sorafenib resistance. Knockout of ABHD12 sensitized liver cancer cells to sorafenib-induced ferroptosis. Co-delivery of sorafenib and ABHD12 inhibitor into a nude mouse model enhanced therapeutic efficacy for LIHC. Our study demonstrates that ABHD12 contributes to tumor growth and sorafenib resistance in liver cancer, which indicate the promising potential of ABHD12 in diagnosis and prognosis as well as highlight the potential therapeutic applications for co-delivery of sorafenib and ABHD12 inhibitor.
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Affiliation(s)
- Mengxing Cai
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Jingwen Luo
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Chunxiu Yang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaopeng Yang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Cheng Zhang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Lixin Ma
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan 430062, China
| | - Yibin Cheng
- State Key Laboratory of Biocatalysis and Enzyme Engineering, Hubei Key Laboratory of Industrial Biotechnology, Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, School of Life Sciences, Hubei University, Wuhan 430062, China
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25
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Ali N, Ferrao K, Mehta KJ. Liver Iron Loading in Alcohol-Associated Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1427-1439. [PMID: 36306827 DOI: 10.1016/j.ajpath.2022.08.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/15/2022] [Accepted: 08/31/2022] [Indexed: 02/04/2023]
Abstract
Alcohol-associated liver disease (ALD) is a common chronic liver disease with increasing incidence worldwide. Alcoholic liver steatosis/steatohepatitis can progress to liver fibrosis/cirrhosis, which can cause predisposition to hepatocellular carcinoma. ALD diagnosis and management are confounded by several challenges. Iron loading is a feature of ALD which can exacerbate alcohol-induced liver injury and promote ALD pathologic progression. Knowledge of the mechanisms that mediate liver iron loading can help identify cellular/molecular targets and thereby aid in designing adjunct diagnostic, prognostic, and therapeutic approaches for ALD. Herein, the cellular mechanisms underlying alcohol-induced liver iron loading are reviewed and how excess iron in patients with ALD can promote liver fibrosis and aggravate disease pathology is discussed. Alcohol-induced increase in hepatic transferrin receptor-1 expression and up-regulation of high iron protein in Kupffer cells (proposed) facilitate iron deposition and retention in the liver. Iron is loaded in both parenchymal and nonparenchymal liver cells. Iron-loaded liver can promote ferroptosis and thereby contribute to ALD pathology. Iron and alcohol can independently elevate oxidative stress. Therefore, a combination of excess iron and alcohol amplifies oxidative stress and accelerates liver injury. Excess iron-stimulated hepatocytes directly or indirectly (through Kupffer cell activation) activate the hepatic stellate cells via secretion of proinflammatory and profibrotic factors. Persistently activated hepatic stellate cells promote liver fibrosis, and thereby facilitate ALD progression.
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Affiliation(s)
- Najma Ali
- GKT School of Medical Education, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Kevin Ferrao
- GKT School of Medical Education, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Kosha J Mehta
- Centre for Education, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
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26
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Wang X, Zhu W, Xing M, Zhu H, Chen E, Zhou J. Matrine disrupts Nrf2/GPX4 antioxidant system and promotes hepatocyte ferroptosis. Chem Biol Interact 2023; 384:110713. [PMID: 37716422 DOI: 10.1016/j.cbi.2023.110713] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 08/14/2023] [Accepted: 09/11/2023] [Indexed: 09/18/2023]
Abstract
Matrine (MT) is an alkaloid isolated from Sophora flavescens with various bioactivities and is widely used clinically. However, the broader its clinical use, the greater its toxicity concerns. We investigate the role of ferroptosis in MT-induced liver injury caused by an imbalance in the antioxidant pathway. Our results showed that MT could cause pathological changes in liver tissues and lead to a significant reduction in L02 cell viability. MT also reduced superoxide dismutase (SOD) and glutathione (GSH), increased malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation levels, and disrupted iron homeostasis, leading to ferroptosis. In addition, MT decreased the protein levels of FTH, Nrf2, xCT, GPX4, HO-1 and ferroptosis suppressor protein 1 (FSP1) and increased the protein levels of TRF1 and DMT1, characteristic indicators of ferroptosis. Interestingly, the cytotoxic effects of MT were alleviated by ferroptosis inhibitor, Nrf2 agonist, or selenium supplementation. These results revealed that MT triggers hepatocyte ferroptosis by inhibiting the Nrf2/GPX4 antioxidant system.
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Affiliation(s)
- Xi Wang
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Wenjing Zhu
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Miao Xing
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Haiyan Zhu
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Enqing Chen
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China
| | - Jie Zhou
- School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun, 336000, PR China.
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27
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Wang Z, Ouyang L, Liu N, Li T, Yan B, Mao C, Xiao D, Gan B, Liu S, Tao Y. The DUBA-SLC7A11-c-Myc axis is critical for stemness and ferroptosis. Oncogene 2023; 42:2688-2700. [PMID: 37537342 DOI: 10.1038/s41388-023-02744-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 05/13/2023] [Accepted: 06/05/2023] [Indexed: 08/05/2023]
Abstract
Ferroptosis is characterized by the accumulation of lipid peroxidation as a unique iron-dependent cell death. However, the interplay between stemness and ferroptosis remains unknown. Here, we demonstrate that undifferentiated cells are more sensitive to ferroptosis than differentiated cells, and cystine transporter SLC7A11 protein is highly up-regulated by deubiquitinase DUBA in differentiated cells. Additionally, DUBA promotes stemness by deubiquitinating SLC7A11. Moreover, SLC7A11 drastically increases the expression of c-Myc through cysteine, the combination of sorafenib and c-Myc inhibitor EN4 has a synergetic effect on cancer therapy. Together, our results reveal that enhanced stemness increases the susceptibility to ferroptosis, and the DUBA-SLC7A11-c-Myc axis is pivotal for differentiated cancer stem cells (CSCs) resistant to ferroptosis, providing a promised targets to eradicate CSCs through ferroptosis.
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Affiliation(s)
- Zuli Wang
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guiyang, Guizhou, 550025, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China
- NHC Key Laboratory of Carcinogenesis of Ministry of Health (Central South University), Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Lianlian Ouyang
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China
- NHC Key Laboratory of Carcinogenesis of Ministry of Health (Central South University), Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Na Liu
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China
- NHC Key Laboratory of Carcinogenesis of Ministry of Health (Central South University), Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Tiansheng Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China
- NHC Key Laboratory of Carcinogenesis of Ministry of Health (Central South University), Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Bokang Yan
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China
- NHC Key Laboratory of Carcinogenesis of Ministry of Health (Central South University), Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Chao Mao
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China
- NHC Key Laboratory of Carcinogenesis of Ministry of Health (Central South University), Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China
| | - Desheng Xiao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
| | - Boyi Gan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shuang Liu
- Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
| | - Yongguang Tao
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China.
- NHC Key Laboratory of Carcinogenesis of Ministry of Health (Central South University), Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China.
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer and Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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Lang Y, Xu S, Zhang C. Hydrothermal Synthesis of Molybdenum Disulfide Quantum Dots for Highly Sensitive Detection of Iron Ions in Protein Succinate Oral Solution. MICROMACHINES 2023; 14:1368. [PMID: 37512679 PMCID: PMC10385574 DOI: 10.3390/mi14071368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/14/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023]
Abstract
In this paper, a molybdenum disulfide fluorescent probe with an Fe3+ fluorescent system was first synthesized by the hydrothermal method for the detection of iron ion concentration in oral solution of protein succinate. It was characterized by infrared, fluorescence, X-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy. The probes were found to have good stability, photobleaching, and storage stability. The effects of dilution, pH, reaction time, and iron ion concentration on the fluorescent system were also investigated. The relative fluorescence intensity [(I0 - I)/I0] showed a good linear relationship with the iron ion concentration in the range of 0-50 μM, with the linear equation [(I0 - I)/I0] = 0.0148[Fe3+] + 0.0833 (r2 = 0.9943, n = 11) and the detection limit of 2.43 μM. The reaction mechanism was also explored, as well as its ion selectivity, reversibility, accuracy, precision, and concentration of Fe ions in the actual sample. It was found that the probe can selectively detect Fe ions with a certain degree of reversibility, accuracy, precision, and ideal recovery, and it can be used for the determination of Fe3+ in proteosuccinic acid oral solution.
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Affiliation(s)
- Yan Lang
- Department of Rehabilitation Therapy, Wuyi University, Nanping 354301, China
| | - Shuru Xu
- Department of Medical Technology, Zhangzhou Health Vocational College/Collaborative Innovation Center for Translation Medical Testing and Application Technology, Zhangzhou 363000, China
| | - Chunbin Zhang
- Department of Medical Technology, Zhangzhou Health Vocational College/Collaborative Innovation Center for Translation Medical Testing and Application Technology, Zhangzhou 363000, China
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Papadopoulos G, Legaki AI, Georgila K, Vorkas P, Giannousi E, Stamatakis G, Moustakas II, Petrocheilou M, Pyrina I, Gercken B, Kassi E, Chavakis T, Pateras IS, Panayotou G, Gika H, Samiotaki M, Eliopoulos AG, Chatzigeorgiou A. Integrated omics analysis for characterization of the contribution of high fructose corn syrup to non-alcoholic fatty liver disease in obesity. Metabolism 2023; 144:155552. [PMID: 36996933 DOI: 10.1016/j.metabol.2023.155552] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 03/17/2023] [Accepted: 03/18/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND High-Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods; its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the molecular mechanisms by which HFCS impacts hepatic metabolism remain scarce, especially in the context of obesity. Besides, the majority of current studies focuses either on the detrimental role of fructose in hepatic steatosis or compare separately the additive impact of fructose versus glucose in high fat diet-induced NAFLD. AIM By engaging combined omics approaches, we sought to characterize the role of HFCS in obesity-associated NAFLD and reveal molecular processes, which mediate the exaggeration of steatosis under these conditions. METHODS Herein, C57BL/6 mice were fed a normal-fat-diet (ND), a high-fat-diet (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic, lipidomic and metabolomic analyses were conducted to identify HFCS-related molecular alterations of the hepatic metabolic landscape in obesity. RESULTS Although HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed aggravation of hepatic steatosis, as analysis of the lipid droplet area in liver sections revealed (12,15 % of total section area in HFD vs 22,35 % in HFD-HFCS), increased NAFLD activity score (3,29 in HFD vs 4,86 in HFD-HFCS) and deteriorated hepatic insulin resistance, as compared to the HFD mice. Besides, the hepatic proteome of HFD-HFCS mice was characterized by a marked upregulation of 5 core proteins implicated in de novo lipogenesis (DNL), while an increased phosphatidyl-cholines(PC)/phosphatidyl-ethanolamines(PE) ratio (2.01 in HFD vs 3.04 in HFD-HFCS) was observed in the livers of HFD-HFCS versus HFD mice. Integrated analysis of the omics datasets indicated that Tricarboxylic Acid (TCA) cycle overactivation is likely contributing towards the intensification of steatosis during HFD-HFCS-induced NAFLD. CONCLUSION Our results imply that HFCS significantly contributes to steatosis aggravation during obesity-related NAFLD, likely deriving from DNL upregulation, accompanied by TCA cycle overactivation and deteriorated hepatic insulin resistance.
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Affiliation(s)
- Grigorios Papadopoulos
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece
| | - Aigli-Ioanna Legaki
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece
| | - Konstantina Georgila
- Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Vorkas
- Institute of Applied Biosciences, Centre for Research and Technology, 57001, Thermi, Thessaloniki, Greece
| | - Eirini Giannousi
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece
| | - George Stamatakis
- Institute for Bio-innovation, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece
| | - Ioannis I Moustakas
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece
| | - Maria Petrocheilou
- School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; Biomic AUTh, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), 57001, Thermi, Thessaloniki, Greece
| | - Iryna Pyrina
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Bettina Gercken
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Ioannis S Pateras
- 2nd Department of Pathology, "Attikon" University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - George Panayotou
- Institute for Bio-innovation, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece
| | - Helen Gika
- School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; Biomic AUTh, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), 57001, Thermi, Thessaloniki, Greece
| | - Martina Samiotaki
- Institute for Bio-innovation, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece
| | - Aristides G Eliopoulos
- Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Center for New Biotechnologies and Precision Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece; Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
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Kitsugi K, Noritake H, Matsumoto M, Hanaoka T, Umemura M, Yamashita M, Takatori S, Ito J, Ohta K, Chida T, Suda T, Kawata K. Simvastatin inhibits hepatic stellate cells activation by regulating the ferroptosis signaling pathway. Biochim Biophys Acta Mol Basis Dis 2023:166750. [PMID: 37268254 DOI: 10.1016/j.bbadis.2023.166750] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 05/03/2023] [Accepted: 05/04/2023] [Indexed: 06/04/2023]
Abstract
BACKGROUND & AIMS Ferroptosis is a form of regulated cell death and its promotion in hepatic stellate cells (HSCs) attenuates liver fibrosis. Statins, which are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may induce ferroptosis via the downregulation of glutathione peroxidase 4 (GPX4) by inhibiting the mevalonate pathway. However, little evidence is available regarding the association between statins and ferroptosis. Therefore, we investigated the association between statins and ferroptosis in HSCs. METHODS Two human HSC cell lines, LX-2 and TWNT-1, were treated with simvastatin, an HMG-CoA reductase inhibitor. Mevalonic acid (MVA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were used to determine the involvement of the mevalonate pathway. We performed a detailed analysis of the ferroptosis signaling pathway. We also investigated human liver tissue samples from patients with nonalcoholic steatohepatitis to clarify the effect of statins on GPX4 expression. RESULTS Simvastatin reduced cell mortality and inhibited HSCs activation, accompanied by iron accumulation, oxidative stress, lipid peroxidation, and reduced GPX4 protein expression. These results indicate that simvastatin inhibits HSCs activation by promoting ferroptosis. Furthermore, treatment with MVA, FPP, or GGPP attenuated simvastatin-induced ferroptosis. These results suggest that simvastatin promotes ferroptosis in HSCs by inhibiting the mevalonate pathway. In human liver tissue samples, statins downregulated the expression of GPX4 in HSCs without affecting hepatocytes. CONCLUSIONS Simvastatin inhibits the activation of HSCs by regulating the ferroptosis signaling pathway.
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Affiliation(s)
- Kensuke Kitsugi
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
| | - Hidenao Noritake
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Moe Matsumoto
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Tomohiko Hanaoka
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masahiro Umemura
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Maho Yamashita
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Shingo Takatori
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Jun Ito
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuyoshi Ohta
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takeshi Chida
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takafumi Suda
- Division of Respiratory Medicine, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuhito Kawata
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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The Emerging Role of Ferroptosis in Liver Cancers. LIFE (BASEL, SWITZERLAND) 2022; 12:life12122128. [PMID: 36556493 PMCID: PMC9788082 DOI: 10.3390/life12122128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/25/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
Liver cancer represents a global health challenge with worldwide growth. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Indeed, approximately 90% of HCC cases have a low survival rate. Moreover, cholangiocarcinoma (CC) is another malignant solid tumor originating from cholangiocytes, the epithelial cells of the biliary system. It is the second-most common primary liver tumor, with an increasing course in morbidity and mortality. Tumor cells always show high metabolic levels, antioxidant modifications, and an increased iron uptake to maintain unlimited growth. In recent years, alterations in iron metabolism have been shown to play an important role in the pathogenesis of HCC. Several findings show that a diet rich in iron can enhance HCC risk. Hence, elevated iron concentration inside the cell may promote the development of HCC. Growing evidence sustains that activating ferroptosis may potentially block the proliferation of HCC cells. Even in CC, it has been shown that ferroptosis plays a crucial role in the treatment of tumors. Several data confirmed the inhibitory effect in cell growth of photodynamic therapy (PDT) that can induce reactive oxygen species (ROS) in CC, leading to an increase in malondialdehyde (MDA) and a decrease in intracellular glutathione (GSH). MDA and GSH depletion/modulation are crucial in inducing ferroptosis, suggesting that PDT may have the potential to induce this kind of cell death through these ways. A selective induction of programmed cell death in cancer cells is one of the main treatments for malignant tumors; thus, ferroptosis may represent a novel therapeutic strategy against HCC and CC.
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Bai J, Liu F. The Yin-Yang functions of macrophages in metabolic disorders. LIFE MEDICINE 2022; 1:319-332. [PMID: 39872753 PMCID: PMC11749365 DOI: 10.1093/lifemedi/lnac035] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 08/29/2022] [Indexed: 01/30/2025]
Abstract
Macrophages are widely distributed in various metabolic tissues/organs and play an essential role in the immune regulation of metabolic homeostasis. Macrophages have two major functions: adaptive defenses against invading pathogens by triggering inflammatory cytokine release and eliminating damaged/dead cells via phagocytosis to constrain inflammation. The pro-inflammatory role of macrophages in insulin resistance and related metabolic diseases is well established, but much less is known about the phagocytotic function of macrophages in metabolism. In this review, we review our current understanding of the ontogeny, tissue distribution, and polarization of macrophages in the context of metabolism. We also discuss the Yin-Yang functions of macrophages in the regulation of energy homeostasis. Third, we summarize the crosstalk between macrophages and gut microbiota. Lastly, we raise several important but remain to be addressed questions with respect to the mechanisms by which macrophages are involved in immune regulation of metabolism.
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Affiliation(s)
- Juli Bai
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
- Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, TX 78229, USA
| | - Feng Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, China
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Ferroptosis: Shedding Light on Mechanisms and Therapeutic Opportunities in Liver Diseases. Cells 2022; 11:cells11203301. [PMID: 36291167 PMCID: PMC9600232 DOI: 10.3390/cells11203301] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/04/2022] [Accepted: 10/13/2022] [Indexed: 11/17/2022] Open
Abstract
Cell death is a vital physiological or pathological phenomenon in the development process of the organism. Ferroptosis is a kind of newly-discovered regulated cell death (RCD), which is different from other RCD patterns, such as apoptosis, necrosis and autophagy at the morphological, biochemical and genetic levels. It is a kind of iron-dependent mode of death mediated by lipid peroxides and lipid reactive oxygen species aggregation. Noteworthily, the number of studies focused on ferroptosis has been increasing exponentially since ferroptosis was first found in 2012. The liver is the organ that stores the most iron in the human body. Recently, it was frequently found that there are different degrees of iron metabolism disorder and lipid peroxidation and other ferroptosis characteristics in various liver diseases. Numerous investigators have discovered that the progression of various liver diseases can be affected via the regulation of ferroptosis, which may provide a potential therapeutic strategy for clinical hepatic diseases. This review aims to summarize the mechanism and update research progress of ferroptosis, so as to provide novel promising directions for the treatment of liver diseases.
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Sun H, Qian X, Yang W, Zhou W, Zhou C, Liu S, Shi H, Tian W. Novel prognostic signature based on HRAS, MAPK3 and TFRC identified to be associated with ferroptosis and the immune microenvironment in hepatocellular carcinoma. Am J Transl Res 2022; 14:6924-6940. [PMID: 36398204 PMCID: PMC9641466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/18/2022] [Indexed: 06/16/2023]
Abstract
OBJECTIVES Ferroptosis, a programmed cell death, has been recognized recently. Several studies have shown the connection between ferroptosis and biological processes in cancer. However, the potential role and mechanism of ferroptosis-related genes in hepatocellular carcinoma (HCC) remain unclear, and understanding the crosstalk between the tumor immune microenvironment and ferroptosis is still a great challenge. METHOD We retrospectively analyzed the transcriptomic and clinical data of HCC from TCGA database. 74 ferroptosis-related genes (FRGs), including 14 immune-ferroptosis-related genes (IFRGs), were identified with differential expression in tumor and normal tissues. Then, we screened and constructed a prognostic signature using survival analysis and the least absolute shrinkage and selection operator. Furthermore, we validated the performance of the signature for assessing survival prognosis and clinicopathological staging. In addition, we investigated the link between the prognostic features and tumor-infiltrating immune cells using CIBERSORT. RESULT The results identified HRAS, MAPK3 and TFRC as prognostic IFRGs. The risk score was elevated when IFRGs were upregulated and patient outcomes worsened. In addition, the results show significant differences in tumor-infiltrating immune cells, especially immunosuppressive cells, including tumor-infiltrating macrophages cells and regulatory cells, implying that the expression of these three IFRGs may be an intrinsic barrier to strong ferritin-induced immune responses. Enrichment analysis revealed crosstalk between ferroptosis and tumor immunity. The effect of the risk score was validated in the ICGC cohort and the Human Protein Atlas database confirmed the high expression of IFRGs in tumor tissue. CONCLUSIONS In our study, these IFRGs may provide some new ideas for the study of ferroptosis and the tumor immunity. These findings may also provide new strategies for treatment of HCC.
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Affiliation(s)
- Hanyao Sun
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Xiyan Qian
- Department of Gerontology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Wei Yang
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Weizhong Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Chungao Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Sheng Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Haibin Shi
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Wei Tian
- Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
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Mitochondrial event as an ultimate step in ferroptosis. Cell Death Dis 2022; 8:414. [PMID: 36209144 PMCID: PMC9547870 DOI: 10.1038/s41420-022-01199-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/15/2022] [Accepted: 09/22/2022] [Indexed: 11/29/2022]
Abstract
In ferroptosis, the roles of mitochondria have been controversial. To explore the role of mitochondrial events in ferroptosis, we employed mitochondrial DNA-depleted ρ0 cells that are resistant to cell death due to enhanced expression of antioxidant enzymes. Expression of mitochondrial-type GPx4 (mGPx4) but no other forms of GPx4 was increased in SK-Hep1 ρ0 cells. Likely due to high mGPx4 expression, SK-Hep1 ρ0 cells were resistant to ferroptosis by erastin inhibiting xCT channel. In contrast, SK-Hep1 ρ0 cells were susceptible to cell death by a high concentration of RSL3 imposing ferroptosis by GPx4 inhibition. Accumulation of cellular ROS and oxidized lipids was observed in erastin- or RSL3-treated SK-Hep1 ρ+ cells but not in erastin-treated SK-Hep1 ρ0 cells. Mitochondrial ROS and mitochondrial peroxidized lipids accumulated in SK-Hep1 ρ+ cells not only by RSL3 but also by erastin acting on xCT on the plasma membrane. Mitochondrial ROS quenching inhibited SK-Hep1 ρ+ cell death by erastin or a high dose of RSL3, suggesting a critical role of mitochondrial ROS in ferroptosis. Ferroptosis by erastin or RSL3 was inhibited by a more than 20-fold lower concentration of MitoQ, a mitochondrial ROS quencher, compared to DecylQ, a non-targeting counterpart. Ferroptosis of SK-Hep1 ρ+ cells by erastin or RSL3 was markedly inhibited by a VDAC inhibitor, accompanied by significantly reduced accumulation of mitochondria ROS, total peroxidized lipids, and mitochondrial peroxidized lipids, strongly supporting the role of mitochondrial events in ferroptotic death and that of VDAC in mitochondrial steps of ferroptosis induced by erastin or RSL3. SK-Hep1 ρ+ cell ferroptosis by sorafenib was also suppressed by mitochondrial ROS quenchers, accompanied by abrogation of sorafenib-induced mitochondrial ROS and mitochondrial peroxidized lipid accumulation. These results suggest that SK-Hep1 ρ0 cells are resistant to ferroptosis due to upregulation of mGPx4 expression and mitochondrial events could be the ultimate step in determining final cell fate.
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Deng H, Zhang J, Zheng Y, Li J, Xiao Q, Wei F, Han W, Xu X, Zhang Y. CCDC25 may be a potential diagnostic and prognostic marker of hepatocellular carcinoma: Results from microarray analysis. Front Surg 2022; 9:878648. [PMID: 36211267 PMCID: PMC9537757 DOI: 10.3389/fsurg.2022.878648] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundHepatocellular carcinoma (HCC) is a tumor with a high recurrence rate, poor prognosis, and rapid progression. Therefore, it is necessary to find a novel biomarker for HCC. Coiled-coil domain containing 25 (CCDC25) has been identified as a target molecule that mediates liver metastasis in colon cancer. However, the molecular mechanisms of CCDC25 in HCC are unknown. This study aimed to explore the role of CCDC25 in HCC.MethodsThe expression of CCDC25 in HCC was identified through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Receiver operating characteristic curve (ROC) curves were drawn to evaluate the diagnostic value of CCDC25 for HCC. The effect of CCDC25 on the prognosis of HCC was analyzed by using the Kaplan–Meier plotter. Co-expressed genes and Gene Set Enrichment Analysis (GSEA) were used to explore the related functions and regulatory signaling pathways of CCDC25. Moreover, we employed the Tumor Immune Estimation Resource (TIMER) database and CIBERSORT algorithm to investigate the relationship between CCDC25 and the tumor immune microenvironment (TME) in HCC. Meanwhile, the effect of CCDC25 on the sensitivity of HCC patients to chemotherapy drugs was evaluated. Finally, we explored the prognostic methylation sites of CCDC25 using the MethSurv database.ResultsCCDC25 expression was low in HCC. Low CCDC25 expression was significantly associated with poor overall survival of HCC and may be comparable to the ability of AFP to diagnose HCC. Dysregulation of glucose metabolism, fatty acid metabolism, amino acid metabolism, ubiquitination modification, and apoptosis inhibition caused by CCDC25 downregulation may be the causes and results of HCC. In addition, CCDC25 was positively correlated with the infiltration level of various adaptive antitumor immune cells. The levels of immune cell infiltration and immune checkpoint expression were lower in the samples with high CCDC25 expression. What is more, we found that downregulated CCDC25 may increase the sensitivity or resistance of HCC patients to multiple drugs, including sorafenib. We also identified a methylation site for CCDC25, which may be responsible for poor prognosis and low CCDC25 expression in HCC patients. Finally, CCDC25 may be associated with HCC ferroptosis.ConclusionsCCDC25 may be a potential diagnostic and prognostic marker for HCC and is associated with immune infiltration and ferroptosis.
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Affiliation(s)
- Hongyang Deng
- Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou, China
| | - Jiaxing Zhang
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yijun Zheng
- Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou, China
| | - Jipin Li
- Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou, China
| | - Qi Xiao
- Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou, China
| | - Fengxian Wei
- Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou, China
| | - Wei Han
- Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou, China
| | - Xiaodong Xu
- Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou, China
| | - Youcheng Zhang
- Department of General Surgery, Hepatic-biliary-pancreatic Institute, Lanzhou University Second Hospital, Lanzhou, China
- Correspondence: Youcheng Zhang
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Chen J, Zhao F, Yang H, Wen J, Tang Y, Wan F, Zhang X, Wu J. Gentian violet induces apoptosis and ferroptosis via modulating p53 and MDM2 in hepatocellular carcinoma. Am J Cancer Res 2022; 12:3357-3372. [PMID: 35968343 PMCID: PMC9360217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 06/29/2022] [Indexed: 06/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancies with limited curative options and poor prognosis. Gentian violet (GV) has recently been found to have anti-tumor properties with promising clinical applications. However, its anti-tumor effect and the underlying functional mechanisms in HCC have not been investigated. In this study, we found that GV induced ferroptosis and apoptosis, inhibited cell proliferation, migration and invasion in a dose-dependent manner in vitro, and significantly attenuated the growth of HCC in vivo. Both ferroptosis inhibitor Ferrostain-1 (Fer-1) and apoptosis inhibitor Z-VAD-KFM (Z-VAD) partially attenuated GV-induced growth-inhibitory effects, while combined treatment of Fer-1 and Z-VAD completely abolished GV's activities. Increased levels of intracellular reactive oxygen species (ROS) were detected after GV treatment. Interestingly, GV elevated the expression levels of both p53 and its negative regulator MDM2, which was dependent on the expression of the dehydrogenase/reductase protein Hep27. Simultaneously silencing both the MDM2 and p53 genes by siRNAs abolished ROS production and partially rescued the cell death induced by GV treatment. Our data demonstrate a GV-Hep27-MDM2-p53 signaling cascade that regulates ferroptosis and apoptosis. Furthermore, our findings provide insights into understanding the anti-tumor function of GV and present the basis of new therapeutic strategies for the treatment of HCC.
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Affiliation(s)
- Jingyi Chen
- College of Basic Medicine, Inner Mongolia Medical UniversityHohhot, Inner Mongolia, China
| | - Fangxin Zhao
- College of Basic Medicine, Inner Mongolia Medical UniversityHohhot, Inner Mongolia, China
- School of Life Sciences, Inner Mongolia UniversityHohhot, Inner Mongolia, China
| | - Hongxin Yang
- College of Basic Medicine, Inner Mongolia Medical UniversityHohhot, Inner Mongolia, China
| | - Jianxun Wen
- College of Basic Medicine, Inner Mongolia Medical UniversityHohhot, Inner Mongolia, China
| | - Ying Tang
- College of Basic Medicine, Inner Mongolia Medical UniversityHohhot, Inner Mongolia, China
| | - Fang Wan
- School of Life Sciences, Inner Mongolia Agricultural UniversityHohhot, Inner Mongolia, China
| | - Xuan Zhang
- College of Basic Medicine, Inner Mongolia Medical UniversityHohhot, Inner Mongolia, China
| | - Jianqiang Wu
- College of Basic Medicine, Inner Mongolia Medical UniversityHohhot, Inner Mongolia, China
- School of Life Sciences, Inner Mongolia UniversityHohhot, Inner Mongolia, China
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Ferroptosis and Its Role in Chronic Diseases. Cells 2022; 11:cells11132040. [PMID: 35805124 PMCID: PMC9265893 DOI: 10.3390/cells11132040] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/23/2022] [Accepted: 06/25/2022] [Indexed: 02/04/2023] Open
Abstract
Ferroptosis, which has been widely associated with many diseases, is an iron-dependent regulated cell death characterized by intracellular lipid peroxide accumulation. It exhibits morphological, biochemical, and genetic characteristics that are unique in comparison to other types of cell death. The course of ferroptosis can be accurately regulated by the metabolism of iron, lipids, amino acids, and various signal pathways. In this review, we summarize the basic characteristics of ferroptosis, its regulation, as well as the relationship between ferroptosis and chronic diseases such as cancer, nervous system diseases, metabolic diseases, and inflammatory bowel diseases. Finally, we describe the regulatory effects of food-borne active ingredients on ferroptosis.
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Peng B, Peng J, Kang F, Zhang W, Peng E, He Q. Ferroptosis-Related Gene MT1G as a Novel Biomarker Correlated With Prognosis and Immune Infiltration in Colorectal Cancer. Front Cell Dev Biol 2022; 10:881447. [PMID: 35517502 PMCID: PMC9065264 DOI: 10.3389/fcell.2022.881447] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/22/2022] [Indexed: 12/13/2022] Open
Abstract
Ferroptosis, a newly discovered way of cell death, has been proved to be involved in the oncogenesis and development of cancers, including colorectal cancer (CRC). Here, by identifying the differentially expressed genes (DEGs) from three CRC transcriptome microarray datasets (GSE20842, GSE23878, and GSE25070), we found that the expression of MT1G was significantly decreased in CRC tissues, and the patients with a high level of MT1G displayed a poor prognosis. Quantitative PCR (qPCR) further confirmed the downregulated MT1G in two CRC cells, HCT8 and HCT116. The colony-forming assay indicated that the MT1G overexpression exhibited a remarkable inhibition of cell proliferation in HCT8 and HCT116 cells. In addition, we explored the co-expressed genes of MT1G to gain a better understanding of its potential signaling pathways. Aberrantly expressed MT1G also affected the immune response of CRC patients. Collectively, these findings might deepen our comprehension on the potential biological implications of MT1G in CRC.
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Affiliation(s)
- Bi Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Jinwu Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- Department of Pathology, Xiangya Changde Hospital, Changde, China
- *Correspondence: Qingchun He, ; Jinwu Peng,
| | - Fanhua Kang
- Department of Pathology, Xiangya Changde Hospital, Changde, China
| | - Wenqin Zhang
- Department of Pathology, Xiangya Changde Hospital, Changde, China
| | - Emin Peng
- Xiangya International Medical Center, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qingchun He
- Department of Emergency, Xiangya Hospital, Central South University, Changsha, China
- Department of Emergency, Xiangya Changde Hospital, Changde, China
- *Correspondence: Qingchun He, ; Jinwu Peng,
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Liu H, Zhao L, Wang M, Yang K, Jin Z, Zhao C, Shi G. FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells. Front Oncol 2022; 12:852095. [PMID: 35392237 PMCID: PMC8980859 DOI: 10.3389/fonc.2022.852095] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/28/2022] [Indexed: 01/16/2023] Open
Abstract
In this study, we aimed to reveal the resistance mechanism of hepatocellular carcinoma (HCC) cells to sorafenib by exploring the effect of FNDC5 on sorafenib-induced ferroptosis in HCC cells. We compared the expression level of FNDC5 between sorafenib-resistant and sorafenib-sensitive HCC cell lines and the level of ferroptosis between the groups after treatment with sorafenib. We knocked down FNDC5 in drug-resistant cell lines and overexpressed it in sorafenib-sensitive HCC cell lines to further demonstrate the role of FNDC5 in sorafenib-induced ferroptosis. Using PI3K inhibitors, we revealed the specific mechanism by which FNDC5 functions. In addition, we verified our findings obtained in in vitro experiments using a subcutaneous tumorigenic nude mouse model. The findings revealed that FNDC5 inhibits sorafenib-induced ferroptosis in HCC cells. In addition, FNDC5 activated the PI3K/Akt pathway, which in turn promoted the nuclear translocation of Nrf2 and increased the intracellular antioxidant response, thereby conferring resistance to ferroptosis. Our study provides novel insights for improving the efficacy of sorafenib.
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Affiliation(s)
- Huayuan Liu
- Department of Hepatobiliary Surgery, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Lei Zhao
- Department of Infection Management, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Mengya Wang
- Department of Physiology, School of Basic Medicine, Institute of Brain Science and Disorders, Qingdao University, Qingdao, China
| | - Kexin Yang
- Department of Gynecology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Zhipeng Jin
- Department of Hepatobiliary Surgery, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Chengjian Zhao
- Department of Hepatobiliary Surgery, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Guangjun Shi
- Department of Hepatobiliary Surgery, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
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Bekric D, Ocker M, Mayr C, Stintzing S, Ritter M, Kiesslich T, Neureiter D. Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation. Cancers (Basel) 2022; 14:1826. [PMID: 35406596 PMCID: PMC8998032 DOI: 10.3390/cancers14071826] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 02/06/2023] Open
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.
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Affiliation(s)
- Dino Bekric
- Center for Physiology, Pathophysiology and Biophysics, Institute for Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (C.M.); (M.R.); (T.K.)
| | - Matthias Ocker
- Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, 55216 Ingelheim, Germany;
- Medical Department, Division of Hematology, Oncology, and Cancer Immunology, Campus Charité Mitte, Charité University Medicine Berlin, 10117 Berlin, Germany;
| | - Christian Mayr
- Center for Physiology, Pathophysiology and Biophysics, Institute for Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (C.M.); (M.R.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/University Hospital Salzburg (SALK), 5020 Salzburg, Austria
| | - Sebastian Stintzing
- Medical Department, Division of Hematology, Oncology, and Cancer Immunology, Campus Charité Mitte, Charité University Medicine Berlin, 10117 Berlin, Germany;
| | - Markus Ritter
- Center for Physiology, Pathophysiology and Biophysics, Institute for Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (C.M.); (M.R.); (T.K.)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University, 5020 Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Tobias Kiesslich
- Center for Physiology, Pathophysiology and Biophysics, Institute for Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (C.M.); (M.R.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/University Hospital Salzburg (SALK), 5020 Salzburg, Austria
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/University Hospital Salzburg (SALK), 5020 Salzburg, Austria
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
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Huang C, Zhan L. Network Pharmacology Identifies Therapeutic Targets and the Mechanisms of Glutathione Action in Ferroptosis Occurring in Oral Cancer. Front Pharmacol 2022; 13:851540. [PMID: 35359830 PMCID: PMC8963897 DOI: 10.3389/fphar.2022.851540] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/23/2022] [Indexed: 01/06/2023] Open
Abstract
Oral cancer (OC) is one of the most pernicious cancers with increasing incidence and mortality worldwide. Surgery is the primary approach for the treatment of early-stage OC, which reduces the quality of life of the patients. Therefore, there is an urgent need to discover novel treatments for OC. Targeting ferroptosis to induce cell death through the modulation of lipid oxidation has been used as a new approach to treat many cancers. Glutathione (GSH) is a coenzyme factor of GSH peroxidase 4, and it carries potential applicability in treating OC. By using network pharmacology and molecular docking followed by systematic bioinformatic analysis, we aimed to study GSH-targeting ferroptosis to treat OC. We identified 14 core molecular targets, namely, EGFR, PTGS2, HIF1A, VEGFA, TFRC, SLC2A1, CAV1, CDKN2A, SLC3A2, IFNG, NOX4, DDIT4, CA9, and DUSP1, involved in ferroptosis that were targeted by GSH for OC treatment. Functional characterization of these molecular targets showed their importance in the control of cell apoptosis, cell proliferation, and immune responses through various kinase activities such as the mitogen-activated protein kinase activity (e.g., ERK1 and ERK2 cascades) and modulation of TOR signaling (e.g., the HIF-1 signaling pathway). Molecular docking further revealed the direct binding of GSH with EGFR, PTGS2, and HIF1A proteins. These findings provide a novel insight into the targets of GSH in ferroptosis as well as possible molecular mechanisms involved, suggesting the possible use of GSH as a combined therapy for treating OC.
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Affiliation(s)
- Chen Huang
- The Center for Data Science in Health and Medicine, Business School, Qingdao University, Qingdao, China
| | - Lei Zhan
- Department of Ophthalmology, The Second People’s Hospital of Guilin, Guilin, China
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Abstract
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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