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Epidemiology of liver diseases:global disease burden and forecasted research trends

Science China Life Sciences 2024年

作者： Jia Xiao Fei Wang Yuan Yuan Jinhang Gao Lu Xiao Chao Yan Feifei Guo Jiajun Zhong Zhaodi Che Wei Li Tian Lan Frank Tacke Vijay H.Shah Cui Li Hua Wang Erdan Dong Division of Gastroenterology and Hepatology Mayo Clinic Department of Health Sciences National Natural Science Foundation of China Department of Oncology The First Affiliated Hospital Institute for Liver Diseases of Anhui Medical University Inflammation and Immune Mediated Diseases Laboratory of Anhui Province Anhui Medical University research Center for Cardiopulmonary Rehabilitation University of Health and Rehabilitation Sciences Qingdao Hospital(Qingdao Municipal Hospital) School of Health and Life Sciences University of Health and Rehabilitation Sciences Department of Cardiology and institute of Vascular Medicine Peking University Third Hospital State Key Laboratory of Vascular Homeostasis and Remodeling Peking University Department of Gastroenterology Qingdao Central Hospital University of Health and Rehabilitation Sciences Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment Zhuhai Hospital Affiliated with Jinan University Division of Gastroenterology Seventh Affiliated Hospital of Sun Yat-sen University School of Biological Sciences Jinan University Aier institute of Ophthalmology Central South University Lab of Gastroenterology and Hepatology West China Hospital Sichuan University Clinical Medicine research institute and Department of Metabolic and Bariatric Surgery the First Affiliated Hospital of Jinan University Faculty of Pharmaceutical Sciences Toho University Department of Hepatology and Gastroenterology Charité-Universit?tsmedizin Berlin Campus Virchow-Klinikum and Campus Charité Mitte

We assessed the global incidence, mortality, and disability-adjusted life years(DALYs) associated with various liver diseases, including alcohol-related liver disease(ALD), hepatitis B/C virus infections(HBV or HCV), liver cancer, metabolic dysfunction-associated steatotic liver disease(MASLD), and other chronic liver diseases, from the 2019 Global Burden of Disease study. Additionally, we analyzed the global trends in hepatology research and drug development. From 2000 to 2019, prevalence rates increased for ALD, MASLD and other liver diseases, while they decreased for HBV, HCV, and liver cancer. Countries with a high socio-demographic index(SDI) exhibited the lowest mortality rates and DALYs. The burden of liver diseases varied due to factors like sex and region. In nine representative countries, MASLD,along with hepatobiliary cancer, showed highest increase in funding in hepatology research. Globally, the major research categories in hepatology papers from 2000 to 2019 were cancer, pathobiology, and MASLD. The United States(U.S.) was at the forefront of hepatology research, with China gradually increasing its influence over time. Hepatologists worldwide are increasingly focusing on studying the communication between the liver and other organs, while underestimating the research on ALD. Cancer, HCV, and MASLD were the primary diseases targeted for therapeutic development in clinical trials. However, the proportion of new drugs approved for the treatment of liver diseases was relatively low among all newly approved drugs in the U.S., China, Japan, and the European Union. Notably, there were no approved drug for the treatment of ALD in the world.

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Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

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Signal Transduction and Targeted Therapy 2024年第1期9卷 105-149页

作者： Yumin Wang Jing Hu Shuang Wu Joshua S.Fleishman Yulin Li Yinshi Xu Wailong Zou Jinhua Wang Yukuan Feng Jichao Chen Hongquan Wang Department of Respiratory and Critical Care Medicine Aerospace Center HospitalPeking University Aerospace School of Clinical MedicineBeijing 100049PR China Department of Pathogen Biology School of Basic Medical SciencesTianjin Medical UniversityTianjin 300060PR China Department of Neurology Zhongnan Hospital of Wuhan UniversityWuhan 430000PR China Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA Department of Outpatient Aerospace Center HospitalPeking University Aerospace School of Clinical MedicineBeijing 100049PR China Beijing Key Laboratory of Drug Target and Screening research Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050PR China Department of Pancreatic Cancer Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060PR China

Ferroptosis,a unique modality of cell death with mechanistic and morphological differences from other cell death modes,plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug *** epigenetic modifications and posttranslational modifications(PTMs)promote anticancer drug resistance,cancer progression,and *** studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases(NSDs),cardiovascular diseases(CVDs),liver diseases,lung diseases,and kidney *** this review,we first summarize the core molecular mechanisms of ***,the roles of epigenetic processes,including histone PTMs,DNA methylation,and noncoding RNA regulation and PTMs,such as phosphorylation,ubiquitination,SUMOylation,acetylation,methylation,and ADP-ribosylation,are concisely *** roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases,including cancers,NSD,CVDs,liver diseases,lung diseases,and kidney diseases,as well as the application of epigenetic and PTM modulators in the therapy of these diseases,are then discussed in *** the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other *** addition,these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

关键词： diseases epigenetic overcome

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Characterization of acute-on-chronic liver diseases: A multicenter prospective cohort study

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World Journal of Hepatology 2024年第5期16卷 809-821页

作者： Yuan-Yao Zhang Sen Luo Hai Li Shu-Ning Sun Xian-Bo Wang Xin Zheng Yan Huang Bei-Ling Li Yan-Hang Gao Zhi-Ping Qian Feng Liu Xiao-Bo Lu Jun-Ping Liu Hao-Tang Ren Yu-Bao Zheng Hua-Dong Yan Guo-Hong Deng Liang Qiao Yan Zhang Wen-Yi Gu Xiao-Mei Xiang Yi Zhou Yi-Xin Hou Qun Zhang Yan Xiong Cong-Cong Zou Jun Chen Ze-Bing Huang Xiu-Hua Jiang Ting-Ting Qi Yuan-Yuan Chen Na Gao Chun-Yan Liu Wei Yuan Xue Mei Jing Li Tao Li Rong-Jiong Zheng Xin-Yi Zhou Jun Zhao Zhong-Ji Meng Department of Infectious Disease Institute of Biomedical ResearchRegulatory Mechanism and Targeted Therapy for Liver Cancer Shiyan Key LaboratoryHubei provincial Clinical Research Center for Precise Diagnosis and Treatment of Liver CancerTaihe HospitalHubei University of MedicineShiyan 442000Hubei ProvinceChina Department of Gastroenterology Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200120China Department of Infectious Diseases Southwest HospitalThe Third Military Medical University(Army Medical University)Chongqing 400000China Center of Integrative Medicine Beijing Ditan HospitalCapital Medical UniversityBeijing 100020China Department of Infectious Diseases Institute of Infection and ImmunologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430020Hubei ProvinceChina Department of Infectious Diseases Hunan Key Laboratory of Viral HepatitisXiangya HospitalCentral South UniversityChangsha 110051Hunan ProvinceChina Hepatology Unit Department of Infectious DiseasesNanfang HospitalSouthern Medical UniversityGuangzhou 510515Guangdong ProvinceChina Department of Hepatology The First Hospital of Jilin UniversityChangchun 130021Jilin ProvinceChina Department of liver Intensive Care Unit Shanghai Public Health Clinical CentreFudan UniversityShanghai 200093China Tianjin institute of Hepatology Nankai University Second People's HospitalTianjin 300192China Infectious Disease Center The First Affiliated Hospital of Xinjiang Medical UniversityUrumqi 830054Xinjiang Uygur Autonomous RegionChina Department of Infectious Diseases and Hepatology The Second Hospital of Shandong UniversityJinan 250000Shandong ProvinceChina State Key Laboratory for Diagnosis and Treatment of Infectious Diseases Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseaseThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000Zhejiang ProvinceChina Department of Infectious Diseases The Thir

BACKGROUND Acute-on-chronic liver disease(AoCLD)accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious *** To explore the characterization of AoCLD to provide theoretical guidance for the accurate diagnosis and prognosis of *** Patients with AoCLD from the Chinese Acute-on-Chronic liver Failure(ACLF)study cohort were included in this *** clinical characteristics and outcomes,and the 90-d survival rate associated with each clinical type of AoCLD were analyzed,using the Kaplan-Meier method and the log-rank *** A total of 3375 patients with AoCLD were enrolled,including 1679(49.7%)patients with liver cirrhosis acute decompensation(LC-AD),850(25.2%)patients with ACLF,577(17.1%)patients with chronic hepatitis acute exacer-bation(CHAE),and 269(8.0%)patients with liver cirrhosis active phase(LC-A).The most common cause of chronic liver disease(CLD)was HBV infection(71.4%).The most common precipitants of AoCLD was bacterial infection(22.8%).The 90-d mortality rates of each clinical subtype of AoCLD were 43.4%(232/535)for type-C ACLF,36.0%(36/100)for type-B ACLF,27.0%(58/215)for type-A ACLF,9.0%(151/1679)for LC-AD,3.0%(8/269)for LC-A,and 1.2%(7/577)for *** HBV infection is the main cause of CLD,and bacterial infection is the main precipitant of *** most common clinical type of AoCLD is *** diagnosis and timely intervention are needed to reduce the mortality of patients with LC-AD or ACLF.

关键词： Acute-on-chronic liver disease Acute-on-chronic liver failure liver cirrhosis Clinical features Prognosis

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Therapeutic strategies for pediatric non-alcoholic fatty liver disease: A challenge for health care providers

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World Journal of Gastroenterology 2007年第18期13卷 2639-2641页

作者： Valerio Nobili Melania Manco liver Unit Bambino Gesù Children's Hospital and Research Institute Rome Italy

Non-alcoholic steato-hepatitis (NASH) is related to insulin resistance and, thus, frequently occurs as part of the metabolic changes that accompany obesity, diabetes and hyperlipidemia. In childhood, the overwhelming boost of obesity and its co-morbidities have lead to the extraordinarily increased prevalence of NASH. Establishing effective therapeutic strategies to treat the disease represents the challenge for hepatologists and gastroenterologists in the next decade. Therapeutic approaches have aimed at treating associated conditions (obesity, insulin resistance, hyperlipemia, etc ) or reducing liver oxidative damage (vitamin E).

关键词： Insulin resistance Non-alcoholic fatty liverdisease Non alcoholic steato-Hepatitis Vitamin E, Diet Thiazolidinediones

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Effects of Xiaoyao San on exercise capacity and liver mitochondrial metabolomics in rat depression model

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Chinese Herbal Medicines 2024年第1期16卷 132-142页

作者： Weidi Zhao Cui Ji Jie Zheng Shi Zhou Junsheng Tian Yumei Han Xuemei Qin School of Physical Education Shanxi UniversityTaiyuan 030006China institute of Biomedicine and Health Shanxi UniversityTaiyuan 030006China Physical Activity Sport and Exercise Research ThemeFaculty of HealthSouthern Cross UniversityLismore NSW2480Australia Modern research Center for Traditional Chinese Medicine Shanxi UniversityTaiyuan 030006China School of Health Yantai Nanshan UniversityYantai 265706China

Objective: This study aimed to investigate the therapeutic effects of Xiaoyao San(XYS), a herbal medicine formula, on exercise capacity and liver mitochondrial metabolomics in a rat model of depression induced by chronic unpredictable mild stress(CUMS).Methods: A total of 24 male SD rats were randomly divided into four groups: control group(C), CUMS control group(M), Venlafaxine positive treatment group(V), and XYS treatment group(X). Depressive behaviour and exercise capacity of rats were assessed by body weight, sugar-water preference test, open field test, pole test, and rotarod test. The liver mitochondria metabolomics were analyzed by using liquid chromatography-mass spectrometry(LC-MS) method. TCMSP database and Gene Cards database were used to screen XYS for potential targets for depression, and GO and KEGG enrichment analyses were ***: Compared with C group, rats in M group showed significantly lower body weight, sugar water preference rate, number of crossing and rearing in the open field test, climbing down time in the pole test,and retention time on the rotarod test(P liver mitochondria of rats in M *** different metabolites and six metabolic pathways were regulated in the liver mitochondria of rats in X group compared with M group. The results of network pharmacology showed that 88 intersecting targets for depression and XYS were obtained, among which 15 key targets such as IL-1β, IL-6, and TNF were predicted to be the main differential targets for the treatment of depression. Additionally, a total of 1 553 GO signaling pathways and 181 KEGG signaling pathways were identified, and the main biological pathways were AGE-RAGE signaling pathway, HIF-1 signaling pathway, and calcium signaling ***

关键词： depression exercise capacity liver mitochondrial metabolomics Xiaoyao San

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Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

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Acta Pharmaceutica Sinica B 2024年第2期14卷 623-634页

作者： Jiacheng Xiong Rongrong Cui Zhaojun Li Wei Zhang Runze Zhang Zunyun Fu Xiaohong Liu Zhenghao Li Kaixian Chen Mingyue Zheng Drug Discovery and Design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China College of Computer and Information Engineering Dezhou UniversityDezhou 253023China AI Department Suzhou Alphama Biotechnology Co.Ltd.Suzhou 215000China Shanghai institute for Advanced Immunochemical Studies and School of Life Science and TechnologyShanghaiTech UniversityShanghai 200031China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Aldehyde oxidase(AOX)is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other ***-mediated metabolism can result in unexpected outcomes,such as the production of toxic metabolites and high metabolic clearance,which can lead to the clinical failure of novel therapeutic *** models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism *** this study,we developed a novel graph neural network called AOMP for predicting AOX-mediated *** integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction,while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both *** significantly outperformed the benchmark methods in both cross-validation and external *** AOMP,we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability,which were validated through in vitro ***,for the convenience of the community,we established the first online service for AOX metabolism prediction based on AOMP,which is freely available at https://***.

关键词： Drugmetabolism Aldehyde oxidase Transferlearning Graph neural network Kinase inhibitor

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LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis

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Genes & Diseases 2024年第3期11卷 417-426页

作者： Zijian Xu Elizabeth R.Davies Liudi Yao Yilu Zhou Juanjuan Li Aiman Alzetani Ben G.Marshall David Hancock Tim Wallis Julian Downward Rob M.Ewing Donna E.Davies Mark G.Jones Yihua Wang Biological Sciences Faculty of Environmental and Life SciencesUniversity of SouthamptonSouthampton SO171BJUK clinical and Experimental Sciences Faculty of MedicineUniversity of SouthamptonSouthampton SO166YDUK institute for Life Sciences University of SouthamptonSouthampton SO171BJUK NIHR Southampton Biomedical research Centre University Hospital SouthamptonSouthampton SO166YDUK University Hospital Southampton Southampton SO166YDUK Oncogene Biology The Francis Crick InstituteLondon NW11ATUK

The factors that determine fibrosis progression or normal tissue repair are largely *** previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition(EMT)in human alveolar epithelial type Il(ATIl)cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine ***,we report that liver kinase B1(LKB1)inactivation in ATIl cells inhibits autophagy and induces EMT as a *** IPF lungs,this is caused by the down-regulation of CAB39L,a key subunit within the LKB1 complex.3D co-cultures of ATIl cells and MRC5 lung fibroblasts coupled with RNA sequencing(RNA-seq)confirmed that paracrine signaling between LKB1-depleted ATIl cells and fibroblasts augmented myofibroblast ***,these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATIl cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.

关键词： CAB39L Crosstalk EMT LKB1 Pulmonary fibrosis

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Palmitoleic acid on top of HFD ameliorates insulin resistance independent of diacylglycerols and alters gut microbiota in C57BL/6J mice

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Food Science and Human Wellness 2024年第2期13卷 856-868页

作者： Qijian Liang Yan Zheng Fanli Meng Xiaofan Jiang Qingcai Zhen Zhongting Lu Shixiu Zhang Lei Du Hao Wu Xin Guo Department of Nutrition and Food Hygiene School of Public HealthCheeloo College of MedicineShandong UniversityJinan 250012China research Center of Translational Medicine Jinan Central Hospital Affiliated to Shandong First Medical UniversityJinan 250013China Department of Hepatology Qilu Hospital of Shandong UniversityJinan 250012China institute of Hepatology Shandong UniversityJinan 250012China

With the prevalence of obesity and obesity-related metabolic syndrome,such as insulin resistance in recent years,it is urgent to explore effective interventions to prevent the progression of obesity-related metabolic *** acid is a monounsaturated fatty acid that is available from dietary sources,mainly derived from marine products.P almitoleic acid plays a positive role in maintaining glucose homeostasis and reducing ***,it is still unknow the mechanism of palmitoleic acid in ameliorating insulin ***,we investigated the effects of palmitoleic acid on chow diet(CD)-fed and high-fat diet(HFD)-fed mice,which were fed CD or HFD for 12 weeks before *** administrated mice with BSA(control),oleic acid,or palmitoleic acid for 6 weeks on top of CD or HFD *** found that palmitoleic acid only improved glucose homeostasis in HFD-fed obese mice by increasing glucose clearance and reducing *** study explored that palmitoleic acid changed the composition of gut microbiota by decreasing Firmicutes population and increasing Bacteroidetes *** colon,palmitoleic acid increased intestinal tight junction integrity and reduced ***,palmitoleic acid decreased macrophage infiltration in liver and adipose tissue and increase glucose uptake in adipose ***(DAG)in tissue(for example,liver)is found to positively correlated with *** enhanced the levels of DAGs in liver but not in adipose tissue in this *** acid did not reverse the high DAG levels induced by HFD in ***,in HFD-fed mice,palmitoleic acid reduced insulin resistance by an independent-manner of *** might be associated with the beneficial effects of palmitoleic acid on altering the gut microbiota composition,improving of intestinal barrier function,and downregulating the inflammation in colon,liver,and adipose tissue.

关键词： Palmitoleic acid High fat diet Insulin resistance Gut microbiota

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Medication beliefs predict medication adherence in ambulatory patients with decompensated cirrhosis

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World Journal of Gastroenterology 2017年第40期23卷 7321-7331页

作者： Kelly L Hayward Patricia C Valery Jennifer H Martin Antara Karmakar Preya J Patel Leigh U Horsfall Caroline J Tallis Katherine A Stuart Penny L Wright David D Smith Katharine M Irvine Elizabeth E Powell W Neil Cottrell Pharmacy Department Princess Al-exandra Hospital The Centre for Liver Disease Research Translational Research Institute The University of Queensland Cancer and Chronic Disease research Group QIMR Berghofer Medical Research Institute School of Medicine and Public Health The University of Newcastle The Centre for liver Disease research Translational Research Institute The University of Queensland Department of Gastroenterology and Hepatology Princess Alexandra Hospital The Centre for Liver Disease Research Translational Research Institute The University of Queensland Department of Gastroenterology and Hepatology Princess Alexandra Hospital Statistics Unit QIMR Berghofer Medical Research Institute School of Pharmacy The University of Queensland

AIM To investigate the impact of medication beliefs, illness perceptions and quality of life on medication adherence in people with decompensated *** One hundred adults with decompensated cirrhosis completed a structured questionnaire when they attended for routine outpatient hepatology review. Measures of self-reported medication adherence(Morisky Medication Adherence Scale), beliefs surrounding medications(Beliefs about Medicines Questionnaire), perceptions of illness and medicines(Brief Illness Perception Questionnaire), and quality of life(Chronic liver Disease Questionnaire) were examined. Clinical data were obtained via patient history and review of medical records. Least absolute shrinkage and selection operator and stepwise backwards regression techniques were used to construct the multivariable logistic regression model. Statistical significance was set at alpha = *** Medication adherence was " High " in 42 % o f participants, "Medium" in 37%, and "Low" in 21%. Compared to patients with "High" adherence, those with "Medium" or "Low" adherence were more likely to report difficulty affording their medications(P < 0.001), lower perception of treatment helpfulness(P = 0.003) and stronger medication concerns relative to medication necessity beliefs(P = 0.003). People with "Low" adherence also experienced greater symptom burden and poorer quality of life, including more frequent abdominal pain(P = 0.023), shortness of breath(P = 0.030), and emotional disturbances(P = 0.050). Multivariable analysis identified having stronger medication concerns relative to necessity beliefs(Necessity-Concerns Differential ≤ 5, OR = 3.66, 95%CI: 1.18-11.40) and more frequent shortness of breath(shortness of breath score ≤ 3, OR = 3.87,95%CI: 1.22-12.25) as independent predictors of "Low"*** The association between "Low" adherence and patients having strong concerns or doubting the necessity or helpfulness of their medications should be explor

关键词： Medication adherence Medication beliefs Illness perceptions Quality of life liver cirrhosis

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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

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Science China Life Sciences 2024年

作者： Chen Xiong Hong Ling Yingdan Huang Hanzhi Dong Bangxiang Xie Qian Hao Xiang Zhou Fudan University Shanghai Cancer Center and institutes of Biomedical Sciences Fudan University Department of Oncology Shanghai Medical College Fudan University Department of Breast Surgery Fudan University Shanghai Cancer Center Fudan University Department of Oncology First Affiliated Hospital of Nanchang University Beijing institute of Hepatology Beijing Youan Hospital Capital Medical University Beijing Engineering research Center for Precision Medicine and Transformation of Hepatitis and liver Cancer Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Fudan University Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology) Institutes of Biomedical Sciences Fudan University

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or siRNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D(Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

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