The muscular system plays a critical role in the human body by governing skeletal movement,cardiovascular function,and the activities of digestive organs.Additionally,muscle tissues serve an endocrine function by secr...The muscular system plays a critical role in the human body by governing skeletal movement,cardiovascular function,and the activities of digestive organs.Additionally,muscle tissues serve an endocrine function by secreting myogenic cytokines,thereby regulating metabolism throughout the entire body.Maintaining muscle function requires iron homeostasis.Recent studies suggest that disruptions in iron metabolism and ferroptosis,a form of iron-dependent cell death,are essential contributors to the progression of a wide range of muscle diseases and disorders,including sarcopenia,cardiomyopathy,and amyotrophic lateral sclerosis.Thus,a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention.This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury,as well as associated muscle diseases and disorders.Moreover,we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders.Finally,we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.展开更多
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 ever...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.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)remains a rapidly growing global health burden.Here,we report that the nonessential amino acid(NEAA)transporter SLC7A11 plays a key role in MASLD.In patie...Metabolic dysfunction-associated steatotic liver disease(MASLD)remains a rapidly growing global health burden.Here,we report that the nonessential amino acid(NEAA)transporter SLC7A11 plays a key role in MASLD.In patients with MASLD,we found high expression levels of SLC7A11 that were correlated directly with clinical grade.Using both loss-of-function and gain-of-function genetic models,we found that Slc7a11 deficiency accelerated MASLD progression via classic cystine/cysteine deficiencyinduced ferroptosis,while serine deficiency and a resulting impairment in de novo cysteine production were attributed to ferroptosis-induced MASLD progression in mice overexpressing hepatic Slc7a11.Consistent with these findings,we found that both serine supplementation and blocking ferroptosis significantly alleviated MASLD,and the serum serine/glutamate ratio was significantly lower in these preclinical disease models,suggesting that it might serve as a prognostic biomarker for MASLD in patients.These findings indicate that defects in NEAA metabolism are involved in the progression of MASLD and that serine deficiency-triggered ferroptosis may provide a therapeutic target for its treatment.展开更多
Both iron metabolism and ferroptosis(an iron-dependent form of programmed cell death)have been connected to the development and progression of many currently incurable non-communicable diseases,including Alzheimer'...Both iron metabolism and ferroptosis(an iron-dependent form of programmed cell death)have been connected to the development and progression of many currently incurable non-communicable diseases,including Alzheimer's disease,Parkinson's disease,multiple sclerosis,Huntington's disease,metabolic dysfunction-associated steatohepatitis,heart failure,and both treatment-relapsed and refractory cancers,such as pancreatic ductal adenocarcinoma and triple-negative breast cancer.Thus,understanding the relationship between iron and these diseases can pave the way for the development of novel therapeutic strategies.Here,we summarize the latest evidence supporting the pathological roles of dysregulated iron metabolism and ferroptosis in a wide range of preclinical animal models of these currently incurable non-communicable diseases.We also summarize the feasibility of targeting iron metabolism and ferroptosis for the prevention and treatment of iron-and ferroptosis-related diseases that currently have limited treatment options.In addition,we provide our perspectives on the challenges and promises regarding the translational potential of targeting dysregulated iron metabolism and ferroptosis to treat diseases,highlighting the future roadmap for developing iron-and ferroptosis-targeted therapeutics.展开更多
The identification of aging-and longevity-associated genes is important for promoting healthy aging.By analyzing a large cohort of Chinese centenarians,we previously found that single-nucleotide polymorphisms(SNPs)in ...The identification of aging-and longevity-associated genes is important for promoting healthy aging.By analyzing a large cohort of Chinese centenarians,we previously found that single-nucleotide polymorphisms(SNPs)in the SLC39A11 gene(also known as ZIP11)are associated with longevity in males.However,the function of the SLC39A11 protein remains unclear.Here,we found that SLC39A11 expression is significantly reduced in patients with Hutchinson-Gilford progeria syndrome(HGPS).In addition,we found that zebrafish with a mutation in slc39a11 that significantly reduces its expression have an accelerated aging phenotype,including a shortened average lifespan,muscle atrophy and reduced swimming,impaired muscle regeneration,gut damage,and abnormal morphology in the reproductive system.Interestingly,these signs of premature aging were more pronounced in male zebrafish than in females.RNA-sequencing analysis revealed that cellular senescence may serve as a potential mechanism for driving this slc39a11 deficiency-induced phenotype in mutant zebrafish.Moreover,immunofluorescence showed significantly increased DNA damage and reactive oxygen species signaling in slc39a11 mutant zebrafish.Using inductively coupled plasma mass spectrometry(ICP-MS),we found that manganese significantly accumulates in slc39a11 mutant zebrafish,as well as in the serum of both global Slc39a11 knockout and hepatocyte-specific Slc39a11 knockout mice,suggesting that this metal transporter regulates systemic manganese levels.Finally,using cultured human fibroblasts,we found that both knocking down SLC39A11 and exposure to high extracellular manganese increased cellular senescence.These findings provide compelling evidence that SLC39A11 serves to protect against the aging process,at least in part by regulating cellular manganese homeostasis.展开更多
Copper dysregulation has been linked to human health,disorders,and hematopoiesis.However,the underlying mechanisms remain elusive.Here,we demonstrate the pivotal role of dietary copper via the transporter Slc31a1(Ctr1...Copper dysregulation has been linked to human health,disorders,and hematopoiesis.However,the underlying mechanisms remain elusive.Here,we demonstrate the pivotal role of dietary copper via the transporter Slc31a1(Ctr1)in copper homeostasis,but not cuproptosis,during postnatal hematopoiesis.Specifically,Slc31a1-mediated copper uptake sustains the differentiation and commitment of multipotent progenitors from short-term hematopoietic stem cells(HSCs).Using transcriptomic analyses,we reveal a disrupted differentiation program in hematopoietic stem and progenitor cells(HSPCs)in diet-induced copper-deficient mice or hematopoietic-specific Slc31a1 knockout(vKO)mice.Further,we show that Slc31a1 and copper are indispensable for sustaining mitochondrial activity via regulating Mtco1 and Mtco2(subunits of Complex IV)within HSPCs.Notably,we show that the chemical compound elesclomol,also well-known as a potent cuproptosis agonist,significantly alleviates severe anemia and partially recovers HSPC mitochondrial function in vKO mice via its activity as a copper ionophore,but with no effect on cuproptosis.We thus renamed elesclomol as CupriActivitor1(CuA1),which is a more specific and descriptive term.These findings demonstrate the critical role and mechanism of copper,Slc31a1,and CuA1 in maintaining HSC homeostasis via modulation of mitochondrial energy metabolism.The study sheds light on the molecular basis of HSC fate decisions by copper or CuA1 and opens new avenues for the development of novel therapeutic strategies for copper-related disorders and blood diseases.Given the critical and multifaceted nature of copper,we propose establishing a novel interdisciplinary field termed“Cuprology”.This discipline will advance our understanding of copper’s roles in physiological and pathological processes.展开更多
Zinc homeostasis plays an essential role in maintaining immune function and is tightly regulated by zinc transporters.We previously reported that the zinc transporter SLC39A10,located in the cell membrane,critically r...Zinc homeostasis plays an essential role in maintaining immune function and is tightly regulated by zinc transporters.We previously reported that the zinc transporter SLC39A10,located in the cell membrane,critically regulates the susceptibility of macrophages to inflammatory stimuli;however,the functional role of SLC39A10 in T cells is currently unknown.Here,we identified two SNPs in SLC39A10 that are associated with inflammatory bowel disease(IBD).We then generated transgenic mice with T cell-specific deletion of Slc39a10(c KO) and found that its loss not only protects against disease progression in IBD and experimental autoimmune encephalomyelitis(EAE),but also induces massive apoptosis via a p53/p21-and Bcl2-independent process.Mechanistically,we show that Slc39a10 serves as a key zinc importer upon activation of T cell receptor to safeguard DNA replication.Together,these findings provide new mechanistic insights and potential targets for the development of new therapeutic strategies for the treatment and/or prevention of T cell-mediated autoimmune diseases.展开更多
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 homeost...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.展开更多
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 f...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.展开更多
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 ha...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.展开更多
Iron,an essential mineral in the body,is involved in numerous physiological processes,making the maintenance of iron homeostasis crucial for overall health.Both iron overload and deficiency can cause various disorders...Iron,an essential mineral in the body,is involved in numerous physiological processes,making the maintenance of iron homeostasis crucial for overall health.Both iron overload and deficiency can cause various disorders and human diseases.Ferroptosis,a form of cell death dependent on iron,is characterized by the extensive peroxidation of lipids.Unlike other kinds of classical unprogrammed cell death,ferroptosis is primarily linked to disruptions in iron metabolism,lipid peroxidation,and antioxidant system imbalance.Ferroptosis is regulated through transcription,translation,and post-translational modifications,which affect cellular sensitivity to ferroptosis.Over the past decade or so,numerous diseases have been linked to ferroptosis as part of their etiology,including cancers,metabolic disorders,autoimmune diseases,central nervous system diseases,cardiovascular diseases,and musculoskeletal diseases.Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable,and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed.Therefore,in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment.In this review,we discuss the physiological significance of iron homeostasis in the body,the potential contribution of ferroptosis to the etiology and development of human diseases,along with the evidence supporting targeting ferroptosis as a therapeutic approach.Importantly,we evaluate recent potential therapeutic targets and promising interventions,providing guidance for future targeted treatment therapies against human diseases.展开更多
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 he...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.展开更多
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-ce...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.展开更多
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 the...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.展开更多
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 wid...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。展开更多
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 ra...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.展开更多
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...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.展开更多
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 gl...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.展开更多
基金the National Natural Science Foundation of China(82471593 to J.M.32330047 and 31930057 to F.W.+2 种基金and 82071970 to Y.W.and 82072506 to Y.L.)the Science Fund for Distinguished Young Scholars of Hubei Province(2023AFA109 to Y.W.)Hubei Provincial Natural Science Foundation of China(2024AFB963 to Q.R.).
文摘The muscular system plays a critical role in the human body by governing skeletal movement,cardiovascular function,and the activities of digestive organs.Additionally,muscle tissues serve an endocrine function by secreting myogenic cytokines,thereby regulating metabolism throughout the entire body.Maintaining muscle function requires iron homeostasis.Recent studies suggest that disruptions in iron metabolism and ferroptosis,a form of iron-dependent cell death,are essential contributors to the progression of a wide range of muscle diseases and disorders,including sarcopenia,cardiomyopathy,and amyotrophic lateral sclerosis.Thus,a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention.This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury,as well as associated muscle diseases and disorders.Moreover,we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders.Finally,we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
基金support from the National Natural Science Foundation of China(No.31930057 to Fudi Wang and No.31970689 to Junxia Min)the National Key R&D Program(No.2018YFA0507801 to Junxia Min and No.2018YFA0507802 to Fudi Wang)the China Postdoctoral Science Foundation(No.2022M712733 to Xue Wang).
文摘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.
基金supported by research grants from the National Natural Science Foundation of China(82471593 to Junxia Min,and 32330047 and 31930057 to Fudi Wang)。
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)remains a rapidly growing global health burden.Here,we report that the nonessential amino acid(NEAA)transporter SLC7A11 plays a key role in MASLD.In patients with MASLD,we found high expression levels of SLC7A11 that were correlated directly with clinical grade.Using both loss-of-function and gain-of-function genetic models,we found that Slc7a11 deficiency accelerated MASLD progression via classic cystine/cysteine deficiencyinduced ferroptosis,while serine deficiency and a resulting impairment in de novo cysteine production were attributed to ferroptosis-induced MASLD progression in mice overexpressing hepatic Slc7a11.Consistent with these findings,we found that both serine supplementation and blocking ferroptosis significantly alleviated MASLD,and the serum serine/glutamate ratio was significantly lower in these preclinical disease models,suggesting that it might serve as a prognostic biomarker for MASLD in patients.These findings indicate that defects in NEAA metabolism are involved in the progression of MASLD and that serine deficiency-triggered ferroptosis may provide a therapeutic target for its treatment.
基金supported by the National Natural Science Foundation of China(82471593 to J.M.32330047,31930057 to F.W.)。
文摘Both iron metabolism and ferroptosis(an iron-dependent form of programmed cell death)have been connected to the development and progression of many currently incurable non-communicable diseases,including Alzheimer's disease,Parkinson's disease,multiple sclerosis,Huntington's disease,metabolic dysfunction-associated steatohepatitis,heart failure,and both treatment-relapsed and refractory cancers,such as pancreatic ductal adenocarcinoma and triple-negative breast cancer.Thus,understanding the relationship between iron and these diseases can pave the way for the development of novel therapeutic strategies.Here,we summarize the latest evidence supporting the pathological roles of dysregulated iron metabolism and ferroptosis in a wide range of preclinical animal models of these currently incurable non-communicable diseases.We also summarize the feasibility of targeting iron metabolism and ferroptosis for the prevention and treatment of iron-and ferroptosis-related diseases that currently have limited treatment options.In addition,we provide our perspectives on the challenges and promises regarding the translational potential of targeting dysregulated iron metabolism and ferroptosis to treat diseases,highlighting the future roadmap for developing iron-and ferroptosis-targeted therapeutics.
基金supported by grants from the National Natural Science Foundation of China(32371222 to Z.X.,32330047 and 31930057 to F.W.,31970689 to J.M.,and 32200961 to Xiaopeng Li)the Zhejiang University School of Public Health Interdisciplinary Research Innovation Team Development Project.
文摘The identification of aging-and longevity-associated genes is important for promoting healthy aging.By analyzing a large cohort of Chinese centenarians,we previously found that single-nucleotide polymorphisms(SNPs)in the SLC39A11 gene(also known as ZIP11)are associated with longevity in males.However,the function of the SLC39A11 protein remains unclear.Here,we found that SLC39A11 expression is significantly reduced in patients with Hutchinson-Gilford progeria syndrome(HGPS).In addition,we found that zebrafish with a mutation in slc39a11 that significantly reduces its expression have an accelerated aging phenotype,including a shortened average lifespan,muscle atrophy and reduced swimming,impaired muscle regeneration,gut damage,and abnormal morphology in the reproductive system.Interestingly,these signs of premature aging were more pronounced in male zebrafish than in females.RNA-sequencing analysis revealed that cellular senescence may serve as a potential mechanism for driving this slc39a11 deficiency-induced phenotype in mutant zebrafish.Moreover,immunofluorescence showed significantly increased DNA damage and reactive oxygen species signaling in slc39a11 mutant zebrafish.Using inductively coupled plasma mass spectrometry(ICP-MS),we found that manganese significantly accumulates in slc39a11 mutant zebrafish,as well as in the serum of both global Slc39a11 knockout and hepatocyte-specific Slc39a11 knockout mice,suggesting that this metal transporter regulates systemic manganese levels.Finally,using cultured human fibroblasts,we found that both knocking down SLC39A11 and exposure to high extracellular manganese increased cellular senescence.These findings provide compelling evidence that SLC39A11 serves to protect against the aging process,at least in part by regulating cellular manganese homeostasis.
基金supported by the National Natural Science Foundation of China(32330047,82471593,32171166,82030003,and 32300988)the China Postdoctoral Science Foundation(M642414).
文摘Copper dysregulation has been linked to human health,disorders,and hematopoiesis.However,the underlying mechanisms remain elusive.Here,we demonstrate the pivotal role of dietary copper via the transporter Slc31a1(Ctr1)in copper homeostasis,but not cuproptosis,during postnatal hematopoiesis.Specifically,Slc31a1-mediated copper uptake sustains the differentiation and commitment of multipotent progenitors from short-term hematopoietic stem cells(HSCs).Using transcriptomic analyses,we reveal a disrupted differentiation program in hematopoietic stem and progenitor cells(HSPCs)in diet-induced copper-deficient mice or hematopoietic-specific Slc31a1 knockout(vKO)mice.Further,we show that Slc31a1 and copper are indispensable for sustaining mitochondrial activity via regulating Mtco1 and Mtco2(subunits of Complex IV)within HSPCs.Notably,we show that the chemical compound elesclomol,also well-known as a potent cuproptosis agonist,significantly alleviates severe anemia and partially recovers HSPC mitochondrial function in vKO mice via its activity as a copper ionophore,but with no effect on cuproptosis.We thus renamed elesclomol as CupriActivitor1(CuA1),which is a more specific and descriptive term.These findings demonstrate the critical role and mechanism of copper,Slc31a1,and CuA1 in maintaining HSC homeostasis via modulation of mitochondrial energy metabolism.The study sheds light on the molecular basis of HSC fate decisions by copper or CuA1 and opens new avenues for the development of novel therapeutic strategies for copper-related disorders and blood diseases.Given the critical and multifaceted nature of copper,we propose establishing a novel interdisciplinary field termed“Cuprology”.This discipline will advance our understanding of copper’s roles in physiological and pathological processes.
基金supported by grants from the National Natural Science Foundation of China (32330047 and 31930057 to F.W.,and 82471593 to J.M.)。
文摘Zinc homeostasis plays an essential role in maintaining immune function and is tightly regulated by zinc transporters.We previously reported that the zinc transporter SLC39A10,located in the cell membrane,critically regulates the susceptibility of macrophages to inflammatory stimuli;however,the functional role of SLC39A10 in T cells is currently unknown.Here,we identified two SNPs in SLC39A10 that are associated with inflammatory bowel disease(IBD).We then generated transgenic mice with T cell-specific deletion of Slc39a10(c KO) and found that its loss not only protects against disease progression in IBD and experimental autoimmune encephalomyelitis(EAE),but also induces massive apoptosis via a p53/p21-and Bcl2-independent process.Mechanistically,we show that Slc39a10 serves as a key zinc importer upon activation of T cell receptor to safeguard DNA replication.Together,these findings provide new mechanistic insights and potential targets for the development of new therapeutic strategies for the treatment and/or prevention of T cell-mediated autoimmune diseases.
基金This work was supported by the National Natural Science Foundation of China(31930057 and 31970689)the National Key Research and Development Program(2018YFA0507802,2018YFA0507801,and 2018YFC2000405).
文摘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.
基金Natural Science Foundation of China(31930057 to F.W.and 31970689 to J.M.).
文摘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.
基金The authors received support from the National Natural Science Foundation of China(31970689 to J.M.,32330047,31930057 to F.W.,and 32100941 to S.S.)the National Key R&D Program(2018YFA0507801 to J.M.and 2018YFA0507802 to F.W.).
文摘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.
基金supported in part by the National Natural Science Foundation of China(31970689 to J.M.,32330047 and 31930057 to F.W.,82071970 to Y.W.and 82072506 to Y.L.)the Science Fund for Distinguished Young Scholars of Hubei Province(2023AFA109 to Y.W.)Hubei Provincial Natural Science Foundation of China(2024AFB971 to Q.R.).
文摘Iron,an essential mineral in the body,is involved in numerous physiological processes,making the maintenance of iron homeostasis crucial for overall health.Both iron overload and deficiency can cause various disorders and human diseases.Ferroptosis,a form of cell death dependent on iron,is characterized by the extensive peroxidation of lipids.Unlike other kinds of classical unprogrammed cell death,ferroptosis is primarily linked to disruptions in iron metabolism,lipid peroxidation,and antioxidant system imbalance.Ferroptosis is regulated through transcription,translation,and post-translational modifications,which affect cellular sensitivity to ferroptosis.Over the past decade or so,numerous diseases have been linked to ferroptosis as part of their etiology,including cancers,metabolic disorders,autoimmune diseases,central nervous system diseases,cardiovascular diseases,and musculoskeletal diseases.Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable,and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed.Therefore,in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment.In this review,we discuss the physiological significance of iron homeostasis in the body,the potential contribution of ferroptosis to the etiology and development of human diseases,along with the evidence supporting targeting ferroptosis as a therapeutic approach.Importantly,we evaluate recent potential therapeutic targets and promising interventions,providing guidance for future targeted treatment therapies against human diseases.
基金supported by research grants from the National Natural Science Foundation of China(31530034 and 31930057 to F.W.,31570791 to J.M.,31701035 to H.W.,31701034 to Q.W.,and 81500984 to L.Y.)the National Key Research and Development Program of China(2018YFA0507802 to F.W.,2018YFA0507801 to J.M.).
文摘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.
基金supported by research grants from the National Natural Science Foundation of China(31600953 to X.Wang31530034 and 31330036 to F.Wang,31570791 and 91542205 to J.Min)+2 种基金the National Key R&D Program of China(2018YFA0507801 to J.Min and 2018YFA0507802 to F.Wang)the Zhejiang Provincial Natural Science Foundation of China(LQ15C110002 to X.Wang and LZ15H160002 to J.Min)the Nation Science and Technology Major Projects for Major New Drugs Innovation and Develop 2017ZX09101-005-004-002(L.Chen).
文摘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.
基金We gratefully acknowledge the financial support provided by the Zhejiang Provincial Key R&D Program of China(2021C02008)the China Agriculture Research System of MOF and MARA(CARS-35)+3 种基金the National Natural Science Foundation of China(Grant Nos.32002185,31930057 and U21A20249)the National Key R&D Program(2018YFA0507802)Taishan Industrial Leading Talents ProjectProgram from National Center of Technology Innovation for Pigs for this study。
文摘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.
基金supported by the National Natural Science Foundation of China(31930057 and 31970689)the National Key Research and Development Program of China(2018YFA0507802 and 2018YFA0507801)the China Postdoctoral Science Foundation(2020TQ0254).
文摘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。
基金This study was supported by research grants from the National Key Research&Develop-ment Program of China(2018YFA0507800 to FW and JM).
文摘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.
基金National Natural Science Foundation of China(81900232 to X.B.,32330047 and 31930057 to F.W.,82471593 to J.M.,81800706 to X.L.)Natural Science Foundation of Zhejiang Province(LQ19H020011 to X.B.)Chinese Postdoctoral Science Foundation(2019M652118 to X.B.).
文摘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.
基金This work was supported by research grants from the National Natural Science Foundation of China(31930057 to F.W.and 31970689 to J.M.).
文摘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.
