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Zooming in and out of ferroptosis in human disease

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Frontiers of Medicine 2023年第2期17卷 173-206页

作者： Xue wang Ye Zhou Junxia Min fudi wang The Second Affiliated Hospital The First Affiliated HospitalInstitute of Translational MedicineSchool of Public HealthState Key Laboratory of Experimental HematologyZhejiang University School of MedicineHangzhou 310058China The First Affiliated Hospital Basic Medical SciencesSchool of Public HealthHengyang Medical SchoolUniversity of South ChinaHengyang 421001China Department of Endocrinology and Metabolism Ningbo First HospitalNingbo 315000China

Ferroptosis is defined as an iron-dependent regulated form of cell death driven by lipid peroxidation.In the past decade,it has been implicated in the pathogenesis of various diseases that together involve almost every organ of the body,including various cancers,neurodegenerative diseases,cardiovascular diseases,lung diseases,liver diseases,kidney diseases,endocrine metabolic diseases,iron-overload-related diseases,orthopedic diseases and autoimmune diseases.Understanding the underlying molecular mechanisms of ferroptosis and its regulatory pathways could provide additional strategies for the management of these disease conditions.Indeed,there are an expanding number of studies suggesting that ferroptosis serves as a bona-fide target for the prevention and treatment of these diseases in relevant pre-clinical models.In this review,we summarize the progress in the research into ferroptosis and its regulatory mechanisms in human disease,while providing evidence in support of ferroptosis as a target for the treatment of these diseases.We also discuss our perspectives on the future directions in the targeting of ferroptosis in human disease.

关键词： ferroptosis human disease iron metabolism lipid peroxidation antioxidation

Targeting ferroptosis opens new avenues for the development of novel therapeutics

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Signal Transduction and Targeted Therapy 2023年第10期8卷 4716-4745页

作者： Shumin Sun Jie Shen Jianwei Jiang fudi wang Junxia Min The First Affiliated Hospital Institute of Translational MedicineThe Second Affiliated HospitalSchoolof Public HealthCancer CenterState Key Laboratory of Experimental HematologyZhejiang University School of MedicineHangzhouChina

Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics,including altered iron homeostasis,reduced defense against oxidative stress,and abnormal lipid peroxidation.Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types,neurodegenerative disease,diseases involving tissue and/or organ injury,and inflammatory and infectious diseases.

关键词： peroxidation diseases homeostasis

Mechanisms and regulation of defensins in host defense

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Signal Transduction and Targeted Therapy 2023年第9期8卷 3985-4014页

作者： Jie Fu Xin Zong Mingliang Jin Junxia Min fudi wang Yizhen wang Key Laboratory of Molecular Animal Nutrition Ministry of EducationCollege of Animal SciencesZhejiang UniversityHangzhouChina Key Laboratory of Animal Nutrition and Feed Science in Eastern China Ministry of AgricultureHangzhouZhejiang ProvinceChina The First Affiliated Hospital Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310058China The Second Affiliated Hospital School of Public HealthState Key Laboratory of Experimental HematologyZhejiang University School of MedicineHangzhouChina The First Affiliated Hospital Basic Medical SciencesSchool of Public HealthHengyang Medical SchoolUniversity of South ChinaHengyangChina

As a family of cationic host defense peptides,defensins are mainly synthesized by Paneth cells,neutrophils,and epithelial cells,contributing to host defense.Their biological functions in innate immunity,as well as their structure and activity relationships,along with their mechanisms of action and therapeutic potential,have been of great interest in recent years.To highlight the key research into the role of defensins in human and animal health,we first describe their research history,structural features,evolution,and antimicrobial mechanisms.Next,we cover the role of defensins in immune homeostasis,chemotaxis,mucosal barrier function,gut microbiota regulation,intestinal development and regulation of cell death.Further,we discuss their clinical relevance and therapeutic potential in various diseases,including infectious disease,inflammatory bowel disease,diabetes and obesity,chronic inflammatory lung disease,periodontitis and cancer.Finally,we summarize the current knowledge regarding the nutrient-dependent regulation of defensins,including fatty acids,amino acids,microelements,plant extracts,and probiotics,while considering the clinical application of such regulation.Together,the review summarizes the various biological functions,mechanism of actions and potential clinical significance of defensins,along with the challenges in developing defensins-based therapy,thus providing crucial insights into their biology and potential clinical utility.

关键词： immunity homeostasis lung

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Bone Research 2023年第1期11卷 1-20页

作者： Qin Ru Yusheng Li Wenqing Xie Yilan Ding Lin Chen Guodong Xu Yuxiang Wu fudi wang Department of Health and Physical Education Jianghan UniversityWuhan430056China Department of Orthopedics Xiangya HospitalCentral South UniversityChangsha410008China National Clinical Research Center for Geriatric Disorders Xiangya HospitalCentral South UniversityChangsha410008China The Second Affiliated Hospital School of Public HealthState Key Laboratory of Experimental HematologyZhejiang University School of MedicineHangzhouChina The First Affiliated Hospital Basic Medical SciencesSchool of Public HealthHengyang Medical SchoolUniversity of South ChinaHengyangChina

Ferroptosis, a unique type of cell death, is characterized by iron-dependent accumulation and lipid peroxidation. It is closely related to multiple biological processes, including iron metabolism, polyunsaturated fatty acid metabolism, and the biosynthesis of compounds with antioxidant activities, including glutathione. In the past 10 years, increasing evidence has indicated a potentially strong relationship between ferroptosis and the onset and progression of age-related orthopedic diseases, such as osteoporosis and osteoarthritis. Therefore, in-depth knowledge of the regulatory mechanisms of ferroptosis in age-related orthopedic diseases may help improve disease treatment and prevention. This review provides an overview of recent research on ferroptosis and its influences on bone and cartilage homeostasis. It begins with a brief overview of systemic iron metabolism and ferroptosis,particularly the potential mechanisms of ferroptosis. It presents a discussion on the role of ferroptosis in age-related orthopedic diseases, including promotion of bone loss and cartilage degradation and the inhibition of osteogenesis. Finally, it focuses on the future of targeting ferroptosis to treat age-related orthopedic diseases with the intention of inspiring further clinical research and the development of therapeutic strategies.

关键词： metabolism diseases peroxidation

Heat Treatment Promotes Ubiquitin-Mediated Proteolysis of SARS-CoV-2 RNA Polymerase and Decreases Viral Load

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Research 2022年第2期2022卷 41-45页

作者： Yasen Maimaitiyiming Tao Yang Qian Qian wang Yan Feng Zhi Chen Mikael Bjorklund fudi wang Chonggao Hu Chih-Hung Hsu Hua Naranmandura Deparment of Public Healh and Department of Hematology of First Afilated Hospital Zhejiang Unvrsity Schoo of MedicineHangzhou 310058China Zhejiang University Cancer Cenler Hangzhou 310058China Deparment of Neurobiology and Depariment of Neurology of the First Afiliated Hospital Zhejiang University School of Medicire.NHC and CAMS Key Laboratory of Medical Neurobiology School of Brain Science and Brain MedicineZhejiang UniversityHangzhou 310058China Zhejing Provincial Center for Disease Control and Prevention Hangzhou 310051China State Key Laboratory for Diagrosis and Treatment of Infectious Diseases Collaborative Innovation Center for DigHosis and Treatment of Infectious DiseaseThe First filiated HospitalZhejiang University School of MedicineHangzhouChina Zhejing Unversity-Univrsity of Edinburgh(ZJU-UoE)Institute Haining 314499ZhejiangChina The First Afiliated Hospital Institute of Trarslational MedicineSchoo of Public HealthZhejiang University School of Medicine.Hangzhou 310058Chima Hengvang Medical School University of South ChinaHengvang 421001China Women's Hospital Institut of Gencticsand Departmrent of Enwironmental Medicine.Zhejiang Universty School of MedicineHangzhou 310006China

Despite extensive eforts,COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large.Vaccination is an eftive approach to curb virus spread,but several variants(eg.delta,delta plus,omicron,and IHU)appear to weaken or possibly escape immune protection.Thus,novel and quickly scalable approaches to restrain SARS-CoV-2 are urgently needed.Mutiple evidences showed thermal sensitivity of SARS-CoV-2 and negative correlation between environmental temperature and COVID-19 transmission with unknown mechanism.Here.we reveal a potential mechanism by which mild heat treatment destabilizes the wild-type RNA-dependent RNA polymerase(also known a nonstructural protein 12(NSP12))of SARS-CoV-2 as well as the P323L mutant commonly found in SARS-CoV-2 variants,including omicron and IHU.Mechanistically,heat treatment promotes E3 ubiquitin ligase ZNF598-dependent NSP12 ubiquitination leading to proteasomal degradation and significantly decreases SARS-CoV-2 RNA copy number and viral titer.A mild daily heat Ireatment maintains low levels of both wild-type and P323L mutant of NSP12,sugesting clinical potential.Collctivel',this novel mechanism,heat-induced NSP12 degradation,suggests a prospective heat-based intervention against SARS-CoV-2.

关键词： NSP1 mechanism delta

Copper homeostasis and cuproptosis in health and disease

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Signal Transduction and Targeted Therapy 2022年第12期7卷 4352-4367页

作者： Liyun Chen Junxia Min fudi wang The Fourth Affiliated Hospital The First Affiliated HospitalInstitute of Translational MedicineSchool of Public HealthState Key Laboratory of Experimental HematologyZhejiang University School of MedicineHangzhouChina The First Affiliated Hospital Basic Medical SciencesSchool of Public HealthHengyang Medical SchoolUniversity of South ChinaHengyangChina

all cell types.Because the accumulation of intracellular copper can induce oxidative stress and perturbing cellular function,copper homeostasis is tightly regulated.Recent studies identified a novel copper-dependent form of cell death called cuproptosis,which is distinct from all other known pathways underlying cell death.Cuproptosis occurs via copper binding to lipoylated enzymes in the tricarboxylic acid(TCA)cycle,which leads to subsequent protein aggregation,proteotoxic stress,and ultimately cell death.Here,we summarize our current knowledge regarding copper metabolism,copper-related disease,the characteristics of cuproptosis,and the mechanisms that regulate cuproptosis.In addition,we discuss the implications of cuproptosis in the pathogenesis of various disease conditions,including Wilson’s disease,neurodegenerative diseases,and cancer,and we discuss the therapeutic potential of targeting cuproptosis.

关键词： homeostasis metabolism diseases

DHODH tangoing with GPX4 on the ferroptotic stage

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Signal Transduction and Targeted Therapy 2021年第7期6卷 1948-1949页

作者： fudi wang Junxia Min The First Affiliated Hospital The Second Affiliated HospitalHengyang Medical SchoolUniversity of South ChinaHengyangChina The First Affiliated Hospital Institute of Translational MedicineCancer CenterSchool of Public HealthZhejiang University School of MedicineHangzhouChina

Ferroptosis,an iron-dependent form of regulated cell death,is prevented by activity of the glutathione-dependent phospholipid hydroperoxidase GPX4(Glutathione peroxidase 4)in the cytosol and mitochondria,and by the glutathione-independent CoQ10 oxidoreductase FSP1 at the plasma membrane.In their recent paper published in Nature,Mao et al.report that DHODH(Dihydroorotate dehydrogenase)coordinates with GPX4 to block ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to form ubiquinol in cancer cells,thus providing a novel targeted strategy for treating cancer.

关键词： CoQ10 death ODH

Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma

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Research 2022年第3期2022卷 367-384页

作者： Hongxiao wang Zijun Song Enjun Xie Junyi Chen Biyao Tang fudi wang Junxia Min The First Affiliated Hospital The Fourth Affiliated HospitalInstitute of Translational MedicineSchool of Public HealthCancer CenterState Key Laboratory of Experimental HematologyZhejiang University School of MedicineHangzhou 310058China The First Affiliated Hospital The Second Affiliated HospitalBasic Medical SciencesSchool of Public HealthSchool of Pharmaceutical ScienceHengyang Medical SchoolUniversity of South ChinaHengyang 421001China Department of Pathology Henan Provincial People’s HospitalPeople’s Hospital of Zhengzhou UniversityPeople’s Hospital of Henan UniversityZhengzhou 450003China

Despite recent advances in the management and treatment of esophageal squamous cell carcinoma(ESCC),the prognosis remains extremely poor,and current nonsurgical treatment options are limited.To identify new therapeutic targets,we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth;similar results were obtained by knocking down both LSD1 and G9a expression.Importantly,we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines.To examine the clinical relevance of these findings,we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues,and this increased expression was significantly correlated with poor prognosis.Mechanistically,we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis,and cotargeting ER stress pathways increased this effect both in vitro and in vivo.Taken together,these findings provide compelling evidence that targeting LSD1,G9a,and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.

关键词： inhibiting Carcinoma viable

Comorbid Chronic Diseases and Acute Organ Injuries Are Strongly Correlated with Disease Severity and Mortality among COVID-19 Patients: A Systemic Review and Meta-Analysis

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Research 2020年第1期2020卷 324-340页

作者： Xinhui wang Xuexian Fang Zhaoxian Cai Xiaotian Wu Xiaotong Gao Junxia Min fudi wang The First Affiliated Hospital School of Public HealthInstitute of Translational MedicineZhejiang University School of MedicineHangzhou 310058China

The recent outbreak of COVID-19 has been rapidly spreading on a global scale.To date,there is no specific vaccine against the causative virus,SARS-CoV-2,nor is there an effective medicine for treating COVID-19,thus raising concerns with respect to the effect of risk factors such as clinical course and pathophysiological parameters on disease severity and outcome in patients with COVID-19.By extracting and analyzing all available published clinical data,we identified several major clinical characteristics associated with increased disease severity and mortality among patients with COVID-19.Specifically,preexisting chronic conditions such as hypertension,cardiovascular disease,chronic kidney disease,and diabetes are strongly associated with an increased risk of developing severe COVID-19;surprisingly,however,we found no correlation between chronic liver disease and increased disease severity.In addition,we found that both acute cardiac injury and acute kidney injury are highly correlated with an increased risk of COVID-19-related mortality.Given the high risk of comorbidity and the high mortality rate associated with tissue damage,organ function should be monitored closely in patients diagnosed with COVID-19,and this approach should be included when establishing new guidelines for managing these high-risk patients.Moreover,additional clinical data are needed in order to determine whether a supportive therapy can help mitigate the development of severe,potentially fatal complications,and further studies are needed to identify the pathophysiology and the mechanism underlying this novel coronavirus-associated infectious disease.Taken together,these findings provide new insights regarding clinical strategies for improving the management and outcome of patients with COVID-19.

关键词： mortality Strongly establishing