Zooming in and out of ferroptosis in human disease

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.

Characterization of ferroptosis-triggered pyroptotic signaling in heart failure

Pressure overload–induced cardiac hypertrophy is a common cause of heart failure(HF),and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes.However,the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown.Here,we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines(PEs)and Acsl4 expression are significantly increased in mice with transverse aortic constriction(TAC)–induced HF compared to sham-operated mice.In addition,we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload‒induced cardiac dysfunction via ferroptosis.Notably,both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF.Moreover,silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus‒induced cell growth.Mechanistically,we found that Acsl4-dependent ferroptosis activates the pyroptotic signaling pathway,which leads to increased production of the proinflammatory cytokine IL-1β,and neutralizing IL-1βimproved cardiac function in Acsl4 transgenic mice following TAC.These results indicate that ACSL4 plays an essential role in the heart during pressure overload‒induced cardiac remodeling via ferroptosis-induced pyroptotic signaling.Together,these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure.

Hepatic HDAC3 Regulates Systemic Iron Homeostasis and Ferroptosis via the Hippo Signaling Pathway

Histone deacetylases(HDACs)are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis.However,whether and how HDACs regulate iron metabolism and ferroptosis(an iron-dependent form of cell death)remain unclear.Here,the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse models.Mice lacking Hdac3 expression in the liver(Hdac3-LKO mice)have significantly reduced hepatic Hamp mRNA(encoding the peptide hormone hepcidin)and altered iron homeostasis.Transcription profiling of Hdac3-LKO mice suggests that the Hippo signaling pathway may be downstream of Hdac3.Moreover,using a Hippo pathway inhibitor and overexpressing the transcriptional regulator Yap(Yes-associated protein)significantly reduced Hamp mRNA levels.Using a promoter reporter assay,we then identified 2 Yap-binding repressor sites within the human HAMP promoter region.We also found that inhibiting Hdac3 led to increased translocation of Yap to the nucleus,suggesting activation of Yap.Notably,knock-in mice expressing a constitutively active form of Yap(Yap K342M)phenocopied the altered hepcidin levels observed in Hdac3-LKO mice.Mechanistically,we show that iron-overload-induced ferroptosis underlies the liver injury that develops in Hdac3-LKO mice,and knocking down Yap expression in Hdac3-LKO mice reduces both iron-overload-and ferroptosis-induced liver injury.These results provide compelling evidence supporting the notion that HDAC3 regulates iron homeostasis via the Hippo/Yap pathway and may serve as a target for reducing ferroptosis in iron-overload-related diseases.

铁稳态代谢分子机制及铁磁纳米颗粒研究进展

铁是人体必需微量元素,参与血红蛋白及多种酶的合成,在氧气运输、免疫调节、核酸合成及基因表达调控等多种生理过程中发挥重要作用.铁稳态代谢的维持对于机体正常生长发育至关重要,铁稳态代谢失衡会引发多种疾病.机体铁稳态代谢的调控由多个环节协调控制;在分子水平上,铁调素Hepcidin作为铁稳态代谢的关键调控因子,通过降解小肠上皮细胞和巨噬细胞上的铁外排蛋白Ferroportin,调控机体铁稳态.由此可见,机体内铁稳态代谢的维持是由多因素、多层次的复杂调控网络协调完成.铁不仅是必需的营养物质,还是新型生物材料的重要组分.铁磁纳米颗粒是一类以铁蛋白或Fe_3O_4等作为基础的生物大分子纳米粒子,因其较强的磁导向性和较好的生物兼容性,已被广泛应用于生物医学领域.本文围绕我们团队近年在铁稳态代谢领域的系列原创发现,就铁调素调控铁代谢稳态的分子网络及铁磁纳米颗粒研究国际前沿进展进行系统综述.

铁过载及铁死亡在心脏疾病中的研究进展

铁作为生命必需的营养元素,在机体组织中的代谢平衡对维持正常的生理功能至关重要.人群流行病学研究和动物实验表明,铁过载在心脏疾病的发生发展过程中发挥重要作用,祛铁可有效缓解心脏疾病进展,但机制尚不清楚.近年来,心脏铁稳态代谢及其分子调控机制获得系列重大进展;铁依赖的新型细胞死亡方式——铁死亡(ferroptosis)概念的提出,为深入理解铁过载与心脏疾病间的关联带来了重要契机.近期,作者团队在国际上率先揭示靶向铁死亡是防控心脏疾病有效措施.本综述系统总结了国内外铁过载与铁死亡对心脏疾病发病的影响及作用机制的最新研究进展,并对未来研究方向进行展望与讨论,旨在为心脏疾病预防和治疗提供新思路与新策略.

Copper homeostasis and cuproptosis in health and disease

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.

The role of iron homeostasis in remodeling immune function and regulating inflammatory disease

The essential trace element iron regulates a wide range of biological processes in virtually all living organisms.Because both iron deficiency and iron overload can lead to various pathological conditions,iron homeostasis is tightly regulated,and understanding this complex process will help pave the way to developing new therapeutic strategies for inflammatory disease.In recent years,significant progress has been made with respect to elucidating the roles of iron and iron-related genes in the development and maintenance of the immune system.Here,we review the timing and mechanisms by which systemic and cellular iron metabolism are regulated during the inflammatory response and during infectious disease,processes in which both the host and the pathogen compete for iron.We also discuss the evidence and implications that immune cells such as macrophages,T cells,and B cells require sufficient amounts of iron for their proliferation and for mediating their effector functions,in which iron serves as a co-factor in toll-like receptor 4(TLR4)signaling,mitochondrial respiration,posttranslational regulation,and epigenetic modification.In addition,we discuss the therapeutic implications of targeting ferroptosis,iron homeostasis and/or iron metabolism with respect to conferring protection against pathogen infection,controlling inflammation,and improving the efficacy of immunotherapy.

The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2

Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.

Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms

Iron homeostasis is essential for health;moreover,hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia.Here,we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells.We validated the results in C57BL/6J mice and a mouse model of hemochromatosis(Hfe^(−/−)mice).Our screen revealed that the anti-rheumatoid arthritis drug auranofin(AUR)potently upregulates hepcidin expression.Interestingly,we found that canonical signaling pathways that regulate iron,including the Bmp/Smad and IL-6/Jak2/Stat3 pathways,play indispensable roles in mediating AUR’s effects.In addition,AUR induces IL-6 via the NF-κB pathway.In C57BL/6J mice,acute treatment with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation.Whereas chronically treating male Hfe^(−/−)mice with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling,decreasing systemic iron overload,but less effective in females.Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells,providing a mechanistic explanation for ineffectiveness of AUR in female Hfe^(−/−)mice.Notably,high-dose AUR(25 mg/kg)induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase(TXNRD)activity.We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by highdose AUR without comprising its beneficial effect on iron metabolism.In conclusion,our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis,and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms,suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.

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

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.

Targeting ferroptosis opens new avenues for the development of novel therapeutics

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.

Ferroptosis:an emerging player in immune cells

Ferroptosis is an iron-dependent form of cell death characterized by an accumulation of lipid peroxides.A growing body of recent evidence supports the notion that ferroptosis plays an important role in mediating a wide variety of cellular processes in diseases.Notably,ferroptosis can play a significant role in mediating various functions in immune cells and immunotherapies.Here,we discuss our current understanding regarding the regulatory role of ferroptosis in immune cells,including T cells,B cells,granulocytes,monocytes,and macrophages.In addition,we discuss the general effect of immune cell ferroptosis on human pathophysiology and immunotherapies,thereby suggesting new strategies for targeting ferroptosis in order to modulate the immune system and unravel the mechanisms that underlie ferroptosis in the immune response。

DHODH tangoing with GPX4 on the ferroptotic stage

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.

Mechanisms and regulation of defensins in host defense

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.

Rewiring ERBB3 and ERK signaling confers resistance to FGFR1 inhibition in gastrointestinal cancer harbored an ERBB3-E928G mutation

Dear Editor,Recently,a large number of studies found that activation of ERBB3(Erb-B2 receptor tyrosine kinase 3,also known as HER3)may be one of the major mechanisms underlying resistance to therapies that target the EGFR(epidermal growth factor receptor),HER2,and other receptor tyrosine kinases(RTKs)(Chen et al.,2011;Choi et al.,2012;Ross et al.,2018).Interestingly,mutations in ERBB3 are commonly reported in gastrointestinal(Gl)cancer,with mutations identified in approximately 12%of stomach and colorectal cancer cases(Jaiswal et al.,2013).

A Systemic Review and Meta-analysis of the Effect of SARS-CoV-2 Infection on Sperm Parameters

Objective.Several studies examined the putativefets of SARS-Cov-2infectionon spem parametersHoweve,the resuls remain controversial.In this study,we conducted the most up-to-date systematic review and meta-analysis to investigate the effect of SARS-CoV-2 infection on sperm quality in COVID-19-positive and COVID-19-negative male participants.Method.Seven databases were searched forliterature released through June 10,2022,containing estimates for the outcomes of interest Using a random-fects model(REM)or a fixed-ffects model(FEM),we analyzed the pooled results.The quality of all included studies was asssed by the Newcastle-Ottawa scale In addition,we performed aquanttative and subgroup analysis of semen data across all included studies.Results.Fourteen studies were extracted from 10 publications,involving a total of 1174 participates for meta-analysis.Sperm parameters of 521 COVID-19 male patients and 653 controls were analyzed.In 8 case-control studies,the pooled mean dfference(MD)of total sperm motility was-5.37%(95%confidence interval(CI):-8.47 to-2.28:<0.05),suggesting that total motility was significantly impaired inmale COVID-19 cases.Subgroup analysis showed a significant decreasein semen volume,sperm concentration,and total motility in 238 patients with arecovery timeof less than 90 days.Moreover,in the other 6 included pre-to post-COVID-19 studies,the pooled MDs of sperm concentration,total sperm count,total motility,progressivemotility,and normal morphology were6.54×10^(6)/ml(95%CI:-10.27 to-2.81;p<0.05),38.89×10^(6)(95%CI:-59.20 to-18.58;p<0.05),-7.21%(95%CI:-14.36 to-0.07;p<0.05),-5.12%(95%CI:-8.71 to-1.53;p<0.05),and-1.52%(95%CI:-2.88 to-0.16;p<0.05),respectively,which indicate SARS-CoV-2 infection significantly affected these five sperm parameters.Conclusion.Our results revealed that SARS-CoV-2 infection was significantly correlated with decreased sperm quality.Of six sperm parameters,total motility and sperm concentration were the most significantly decreased parameters.These results suggest a possible negative influence of SARS-CoV-2 infection on testicular function and male fertility.Given the potential detrimental effect of SARS-CoV-2 on semen quality,male reproductive health should be monitored closely in patients with COVID-19.This trial is registered with CRD42021275823.

Macrophage-Mediated Defensive Mechanisms Involving Zinc Homeostasis in Bacterial Infection

Zinc homeostasis in macrophages is essential for maintaining their antimicrobial functions,and a growing body of evidence indicates that both zinc depletion and excess zinc in myeloid cells decrease bacterial survival.In macrophages,maintaining intracellular and extracellular zinc levels via zinc transporter proteins,including Slc30a and Slc39a family members,plays an important role in the response to immunological signals and infection.Recently,studies have found that macrophages utilize a variety of zinc-modulating mechanisms,thus expanding our knowledge regarding the role that zinc plays in response to bacterial infection.Here,we review recent progress with respect to altered zinc metabolism in macrophages and the consequences with respect to fighting invading pathogens.

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

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.