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Anastasopoulos NA, Barbouti A, Goussia AC, Christodoulou DK, Glantzounis GK. Exploring the Role of Metabolic Hyperferritinaemia (MHF) in Steatotic Liver Disease (SLD) and Hepatocellular Carcinoma (HCC). Cancers (Basel) 2025; 17:842. [PMID: 40075688 PMCID: PMC11899477 DOI: 10.3390/cancers17050842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
The increasing prevalence of the spectrum of Steatotic Liver Disease (SLD), including Metabolic-Associated Steatotic Liver Disease (MASLD), Metabolic-Associated Steatohepatitis (MASH), and progression to Cirrhosis and Hepatocellular Carcinoma (HCC) has led to intense research in disease pathophysiology, with many studies focusing on the role of iron. Iron overload, which is often observed in patients with SLD as a part of metabolic hyperferritinaemia (MHF), particularly in the reticuloendothelial system (RES), can exacerbate steatosis. This imbalance in iron distribution, coupled with a high-fat diet, can further promote the progression of SLD by means of oxidative stress triggering inflammation and activating hepatic stellate cells (HSCs), therefore leading to fibrosis and progression of simple steatosis to the more severe MASH. The influence of iron overload in disease progression has also been shown by the complex role of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. Ferroptosis depletes the liver's antioxidant capacity, further contributing to the development of MASH, while its role in MASH-related HCC is potentially linked to alternations in the tumour microenvironment, as well as ferroptosis resistance. The iron-rich steatotic hepatic environment becomes prone to hepatocarcinogenesis by activation of several pro-carcinogenic mechanisms including epithelial-to-mesenchymal transition and deactivation of DNA damage repair. Biochemical markers of iron overload and deranged metabolism have been linked to all stages of SLD and its associated HCC in multiple patient cohorts of diverse genetic backgrounds, enhancing our daily clinical understanding of this interaction. Further understanding could lead to enhanced therapies for SLD management and prevention.
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Affiliation(s)
- Nikolaos-Andreas Anastasopoulos
- HPB Unit, Department of Surgery, University Hospital of Ioannina, 45110 Ioannina, Greece
- Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, London W12 0HS, UK
| | - Alexandra Barbouti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
| | - Anna C. Goussia
- Department of Pathology, University Hospital of Ioannina, 45110 Ioannina, Greece
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Liu WY, Lian LY, Zhang H, Chen SD, Jin XZ, Zhang N, Ye CH, Chen WY, Bee GGB, Wang FD, Miele L, Corradini E, Valenti L, Zheng MH. A Population-Based and Clinical Cohort Validation of the Novel Consensus Definition of Metabolic Hyperferritinemia. J Clin Endocrinol Metab 2024; 109:1540-1549. [PMID: 38124275 PMCID: PMC11099479 DOI: 10.1210/clinem/dgad749] [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: 09/28/2023] [Revised: 12/09/2023] [Accepted: 12/18/2023] [Indexed: 12/23/2023]
Abstract
CONTEXT There is limited data on the clinical significance of metabolic hyperferritinemia (MHF) based on the most recent consensus. OBJECTIVE We aimed to validate the clinical outcomes of MHF in the general population and patients with biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS The NHANES database and PERSONS cohort were included. MHF was defined as elevated serum ferritin with metabolic dysfunction (MD) and stratified into different grades according to ferritin (grade 1: 200 [females]/300 [males]-550 ng/mL; grade 2: 550-1000 ng/mL; grade 3: >1000 ng/mL). The clinical outcomes, including all-cause death, comorbidities, and liver histology, were compared between non-MHF and MHF in adjusted models. RESULTS In NHANES, compared with non-MHF with MD, MHF was related to higher risks of advanced fibrosis (P = .036), elevated albumin-creatinine ratio (UACR, P = .001), and sarcopenia (P = .013). Although the association between all grades of MHF and mortality was insignificant (P = .122), grades 2/3 was associated with increased mortality (P = .029). When comparing with non-MHF without MD, the harmful effects of MHF were more significant in mortality (P < .001), elevated UACR (P < .001), cardiovascular disease (P = .028), and sarcopenia (P < .001). In the PERSONS cohort, MHF was associated with more advanced grades of steatosis (P < .001), lobular inflammation (P < .001), advanced fibrosis (P = .017), and more severe hepatocellular iron deposition (P < .001). CONCLUSION Both in the general population and in at-risk individuals with MAFLD, MHF was related with poorer clinical outcomes.
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Affiliation(s)
- Wen-Yue Liu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Wenzhou Key Laboratory of Diabetes Research, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Li-You Lian
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Huai Zhang
- Biostatistics and Medical Quality Management Office, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Sui-Dan Chen
- Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Xin-Zhe Jin
- Department of Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Ni Zhang
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Chen-Hui Ye
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - Wen-Ying Chen
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
| | - George Goh Boon Bee
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore 169608, Singapore
| | - Fu-Di Wang
- The Fourth Affiliated Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310000, China
- The First Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421001, China
| | - Luca Miele
- Department of Internal Medicine Medical and Surgical Sciences, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica di Roma, Rome 00168, Italy
| | - Elena Corradini
- Department of Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena 41100, Italy
- Internal Medicine and Centre for Hemochromatosis and Hereditary Liver Diseases, Azienda Ospedaliero-Universitaria di Modena-Policlinico, Modena 41100, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan 20121, Italy
- Biological Resource Center and Precision Medicine Lab, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Milan 20121, Italy
- Department of Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Milan 20121, Italy
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou 325000, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou 325000, China
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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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Qu WF, Tian MX, Qiu JT, Guo YC, Tao CY, Liu WR, Tang Z, Qian K, Wang ZX, Li XY, Hu WA, Zhou J, Fan J, Zou H, Hou YY, Shi YH. Exploring pathological signatures for predicting the recurrence of early-stage hepatocellular carcinoma based on deep learning. Front Oncol 2022; 12:968202. [PMID: 36059627 PMCID: PMC9439660 DOI: 10.3389/fonc.2022.968202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/04/2022] [Indexed: 12/24/2022] Open
Abstract
BackgroundPostoperative recurrence impedes the curability of early-stage hepatocellular carcinoma (E-HCC). We aimed to establish a novel recurrence-related pathological prognosticator with artificial intelligence, and investigate the relationship between pathological features and the local immunological microenvironment.MethodsA total of 576 whole-slide images (WSIs) were collected from 547 patients with E-HCC in the Zhongshan cohort, which was randomly divided into a training cohort and a validation cohort. The external validation cohort comprised 147 Tumor Node Metastasis (TNM) stage I patients from The Cancer Genome Atlas (TCGA) database. Six types of HCC tissues were identified by a weakly supervised convolutional neural network. A recurrence-related histological score (HS) was constructed and validated. The correlation between immune microenvironment and HS was evaluated through extensive immunohistochemical data.ResultsThe overall classification accuracy of HCC tissues was 94.17%. The C-indexes of HS in the training, validation and TCGA cohorts were 0.804, 0.739 and 0.708, respectively. Multivariate analysis showed that the HS (HR= 4.05, 95% CI: 3.40-4.84) was an independent predictor for recurrence-free survival. Patients in HS high-risk group had elevated preoperative alpha-fetoprotein levels, poorer tumor differentiation and a higher proportion of microvascular invasion. The immunohistochemistry data linked the HS to local immune cell infiltration. HS was positively correlated with the expression level of peritumoral CD14+ cells (p= 0.013), and negatively with the intratumoral CD8+ cells (p< 0.001).ConclusionsThe study established a novel histological score that predicted short-term and long-term recurrence for E-HCCs using deep learning, which could facilitate clinical decision making in recurrence prediction and management.
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Affiliation(s)
- Wei-Feng Qu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Meng-Xin Tian
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing-Tao Qiu
- Tsimage Medical Technology, Yihai Center, Shenzhen, China
| | - Yu-Cheng Guo
- Tsimage Medical Technology, Yihai Center, Shenzhen, China
| | - Chen-Yang Tao
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Wei-Ren Liu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Zheng Tang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Kun Qian
- Department of Information and Intelligence Development, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhi-Xun Wang
- Department of Information and Intelligence Development, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Yu Li
- Tsimage Medical Technology, Yihai Center, Shenzhen, China
| | - Wei-An Hu
- Tsimage Medical Technology, Yihai Center, Shenzhen, China
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
| | - Hao Zou
- Tsimage Medical Technology, Yihai Center, Shenzhen, China
- Center for Intelligent Medical Imaging & Health, Research Institute of Tsinghua University in Shenzhen, Shenzhen, China
- *Correspondence: Ying-Hong Shi, ; Ying-Yong Hou, ; Hao Zou,
| | - Ying-Yong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- *Correspondence: Ying-Hong Shi, ; Ying-Yong Hou, ; Hao Zou,
| | - Ying-Hong Shi
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
- *Correspondence: Ying-Hong Shi, ; Ying-Yong Hou, ; Hao Zou,
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Tsuchiya H. Iron-Induced Hepatocarcinogenesis—Preventive Effects of Nutrients. Front Oncol 2022; 12:940552. [PMID: 35832553 PMCID: PMC9271801 DOI: 10.3389/fonc.2022.940552] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/03/2022] [Indexed: 01/10/2023] Open
Abstract
The liver is a primary organ that stores body iron, and plays a central role in the regulation of iron homeostasis. Hepatic iron overload (HIO) is a prevalent feature among patients with chronic liver diseases (CLDs), including alcoholic/nonalcoholic liver diseases and hepatitis C. HIO is suggested to promote the progression toward hepatocellular carcinoma because of the pro-oxidant nature of iron. Iron metabolism is tightly regulated by various factors, such as hepcidin and ferroportin, in healthy individuals to protect the liver from such deteriorative effects. However, their intrinsic expressions or functions are frequently compromised in patients with HIO. Thus, various nutrients have been reported to regulate hepatic iron metabolism and protect the liver from iron-induced damage. These nutrients are beneficial in HIO-associated CLD treatment and eventually prevent iron-mediated hepatocarcinogenesis. This mini-review aimed to discuss the mechanisms and hepatocarcinogenic risk of HIO in patients with CLDs. Moreover, nutrients that hold the potential to prevent iron-induced hepatocarcinogenesis are summarized.
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Liu S, Cao X, Wang D, Zhu H. Iron metabolism: State of the art in hypoxic cancer cell biology. Arch Biochem Biophys 2022; 723:109199. [DOI: 10.1016/j.abb.2022.109199] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 02/08/2023]
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Yu YC, Luu HN, Wang R, Thomas CE, Glynn NW, Youk AO, Behari J, Yuan JM. Serum Biomarkers of Iron Status and Risk of Hepatocellular Carcinoma Development in Patients with Nonalcoholic Fatty Liver Disease. Cancer Epidemiol Biomarkers Prev 2022; 31:230-235. [PMID: 34649958 PMCID: PMC9204666 DOI: 10.1158/1055-9965.epi-21-0754] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/27/2021] [Accepted: 10/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has become a major contributor to the rising incidence of hepatocellular carcinoma (HCC) in the United States and other developed countries. Iron, an essential metal primarily stored in hepatocytes, may play a role in the development of NAFLD-related HCC. Epidemiologic data on iron overload without hemochromatosis in relation to HCC are sparse. This study aimed to examine the associations between serum biomarkers of iron and the risk of HCC in patients with NAFLD. METHODS We identified 18,569 patients with NAFLD using the University of Pittsburgh Medical Center electronic health records from 2004 through 2018. After an average 4.34 years of follow-up, 244 patients developed HCC. Cox proportional hazard regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) of HCC incidence associated with elevated levels of iron biomarkers with adjustment for age, sex, race, body mass index, history of diabetes, and tobacco smoking. RESULTS The HRs (95% CIs) of HCC for clinically defined elevation of serum iron and transferrin saturation were 2.91 (1.34-6.30) and 2.02 (1.22-3.32), respectively, compared with their respective normal range. No statistically significant association was observed for total iron-binding capacity or serum ferritin with HCC risk. CONCLUSIONS Elevated levels of serum iron and transferrin saturation were significantly associated with increased risk of HCC among patients with NAFLD without hemochromatosis or other major underlying causes of chronic liver diseases. IMPACT Clinical surveillance of serum iron level may be a potential strategy to identify patients with NAFLD who are at high risk for HCC.
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Affiliation(s)
- Yi-Chuan Yu
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Hung N Luu
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Renwei Wang
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Claire E Thomas
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Nancy W Glynn
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ada O Youk
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jaideep Behari
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jian-Min Yuan
- Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
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Petrillo S, Manco M, Altruda F, Fagoonee S, Tolosano E. Liver Sinusoidal Endothelial Cells at the Crossroad of Iron Overload and Liver Fibrosis. Antioxid Redox Signal 2021; 35:474-486. [PMID: 32689808 DOI: 10.1089/ars.2020.8168] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Significance: Liver fibrosis results from different etiologies and represents one of the most serious health issues worldwide. Fibrosis is the outcome of chronic insults on the liver and is associated with several factors, including abnormal iron metabolism. Recent Advances: Multiple mechanisms underlying the profibrogenic role of iron have been proposed. The pivotal role of liver sinusoidal endothelial cells (LSECs) in iron-level regulation, as well as their morphological and molecular dedifferentiation occurring in liver fibrosis, has encouraged research on LSECs as prime regulators of very early fibrotic events. Importantly, normal differentiated LSECs may act as gatekeepers of fibrogenesis by maintaining the quiescence of hepatic stellate cells, while LSECs capillarization precedes the onset of liver fibrosis. Critical Issues: In the present review, the morphological and molecular alterations occurring in LSECs after liver injury are addressed in an attempt to highlight how vascular dysfunction promotes fibrogenesis. In particular, we discuss in depth how a vicious loop can be established in which iron dysregulation and LSEC dedifferentiation synergize to exacerbate and promote the progression of liver fibrosis. Future Directions: LSECs, due to their pivotal role in early liver fibrosis and iron homeostasis, show great promises as a therapeutic target. In particular, new strategies can be devised for restoring LSECs differentiation and thus their role as regulators of iron homeostasis, hence preventing the progression of liver fibrosis or, even better, promoting its regression. Antioxid. Redox Signal. 35, 474-486.
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Affiliation(s)
- Sara Petrillo
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Marta Manco
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Fiorella Altruda
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, CNR c/o Molecular Biotechnology Center, Torino, Italy
| | - Emanuela Tolosano
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
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Weiler S, Nairz M. TAM-ing the CIA-Tumor-Associated Macrophages and Their Potential Role in Unintended Side Effects of Therapeutics for Cancer-Induced Anemia. Front Oncol 2021; 11:627223. [PMID: 33842333 PMCID: PMC8027083 DOI: 10.3389/fonc.2021.627223] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 03/01/2021] [Indexed: 12/21/2022] Open
Abstract
Cancer-induced anemia (CIA) is a common consequence of neoplasia and has a multifactorial pathophysiology. The immune response and tumor treatment, both intended to primarily target malignant cells, also affect erythropoiesis in the bone marrow. In parallel, immune activation inevitably induces the iron-regulatory hormone hepcidin to direct iron fluxes away from erythroid progenitors and into compartments of the mononuclear phagocyte system. Moreover, many inflammatory mediators inhibit the synthesis of erythropoietin, which is essential for stimulation and differentiation of erythroid progenitor cells to mature cells ready for release into the blood stream. These pathophysiological hallmarks of CIA imply that the bone marrow is not only deprived of iron as nutrient but also of erythropoietin as central growth factor for erythropoiesis. Tumor-associated macrophages (TAM) are present in the tumor microenvironment and display altered immune and iron phenotypes. On the one hand, their functions are altered by adjacent tumor cells so that they promote rather than inhibit the growth of malignant cells. As consequences, TAM may deliver iron to tumor cells and produce reduced amounts of cytotoxic mediators. Furthermore, their ability to stimulate adaptive anti-tumor immune responses is severely compromised. On the other hand, TAM are potential off-targets of therapeutic interventions against CIA. Red blood cell transfusions, intravenous iron preparations, erythropoiesis-stimulating agents and novel treatment options for CIA may interfere with TAM function and thus exhibit secondary effects on the underlying malignancy. In this Hypothesis and Theory, we summarize the pathophysiological hallmarks, clinical implications and treatment strategies for CIA. Focusing on TAM, we speculate on the potential intended and unintended effects that therapeutic options for CIA may have on the innate immune response and, consequently, on the course of the underlying malignancy.
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Affiliation(s)
- Stefan Weiler
- National Poisons Information Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland.,Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Eidgenossische Technische Hochschule Zurich, Zurich, Switzerland
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
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The Effects of Dandelion Polysaccharides on Iron Metabolism by Regulating Hepcidin via JAK/STAT Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:7184760. [PMID: 33488942 PMCID: PMC7801049 DOI: 10.1155/2021/7184760] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 11/29/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023]
Abstract
Recent studies have claimed that iron overload was correlated with the risk of hepatocellular carcinoma (HCC), and our previous studies have also demonstrated that dandelion polysaccharide (DP) suppressed HCC cell line proliferation via causing cell cycle arrest and inhibiting the PI3K/AKT/mTOR pathway, but the effect of DP on metabolism is still not very clear. Here, we aim to clarify the effects of DP on iron metabolism and the underlying mechanism. In this study, we found that DP could reduce iron burden in hepatoma cells and grafted tumors. Hepcidin is a central regulator in iron metabolism. We confirmed that the expression of hepcidin in HCC tumor tissues was significantly higher than that in the adjacent nontumor tissues. The expression of hepcidin was downregulated in the liver of mouse model treatment with DP, as well as in hepatoma cells. Moreover, RNA sequencing and western blot data revealed that DP inhibited the IL-6-activated JAK-STAT signaling pathway. In summary, our results revealed that DP might be a new potential drug candidate for the regulation of iron burden and the treatment of HCC.
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