Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an imp...Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.展开更多
Objective This study investigated the effect of reducing soluble epoxide hydrolase(sEH,encoded by the Ephx2 gene)on the mediation of EETs metabolism during ferroptosis in emphysema in vivo.Methods Male C57BL/6J wild-t...Objective This study investigated the effect of reducing soluble epoxide hydrolase(sEH,encoded by the Ephx2 gene)on the mediation of EETs metabolism during ferroptosis in emphysema in vivo.Methods Male C57BL/6J wild-type(WT)and Ephx2^(-/-)mice received whole-body exposure to either cigarette smoke(CS)or air for 16 weeks.The alveolar structure,pulmonary function,lung tissue morphology,cell death,and ferroptosis levels were assessed following exposure.Results CS exposure caused emphysema,reduced pulmonary function,and induced ferroptosis in mice compared with exposure to air.In contrast,following CS exposure,Ephx2^(-/-)mice exhibited significantly lower levels of emphysema,impaired lung function,lung cell death,intracellular iron,lipid reactive oxygen species,cyclooxygenase-2,4-hydroxynonenal,and malondialdehyde levels than those of WT mice.However,Ephx2^(-/-)mice exhibited higher levels of glutathione and ferritin heavy chain 1 than those of WT mice.SLC7A11 expression was significantly reduced,whereas glutathione peroxidase 4 expression was markedly increased in Ephx2^(-/-)mice compared with WT mice.Statistically significant differences(P<0.05)were observed.Conclusion These results suggest that Ephx2 deficiency inhibits ferroptosis to alleviate CS-induced emphysema,primarily by mitigating its inhibitory effect on the cystine/glutathione/glutathione peroxidase 4 axis.Therefore,Ephx2 represents an effective therapeutic target in CS-induced chronic obstructive pulmonary disease(COPD).展开更多
As one of the key targets of tumor metabolic therapy,glucose dyshomeostasis by disrupting glucose metabolism possesses the potential to reverse therapeutic resistance of a variety of regulated cell deaths(RCDs),but th...As one of the key targets of tumor metabolic therapy,glucose dyshomeostasis by disrupting glucose metabolism possesses the potential to reverse therapeutic resistance of a variety of regulated cell deaths(RCDs),but the functional pathways are not fully revealed and employed.Herein,we demonstrate that the intervention on SLC7A11/GSH/GPX4 antioxidant axis by glucose dyshomeostasis can simultaneously promote disulfidptosis,cuproptosis and ferroptosis,which is verified by employing glucose oxidase(GOx)-modified copper-apigenin(CuAp)network nanoshuttles(CuAp@GOx NSs)in ovarian tumor therapy.Ap and GOx can jointly induce glucose dyshomeostasis respectively by inhibiting glucose transporter 1-mediated glucose uptake upstream,and consuming massive glucose downstream.As a result of glucose dyshomeostasis,the NADPH supplement is downregulated,which further disrupts SLC7A11/GSH/GPX4 antioxidant axis.This simultaneously boosts disulfidptosis by facilitating cystine accumulation,cuproptosis by attenuating GSH-mediated Cu+inactivation,and ferroptosis by downregulating GPX4 expression.Owing to the combination of disulfidptosis,cuproptosis and ferroptosis,CuAp@GOx NSs exhibit good efficacy in treating ovarian tumor model.This work proposes an alternative strategy for tumor therapy based on glucose dyshomeostasis,which mainly targets the RCDs relating to SLC7A11/GSH/GPX4 axis.展开更多
Tendinopathy is a common and complex musculoskeletal disorder,unfortunately current clinical strategies for tendinopathy have low therapeutic efficacy because of complicated pathogenesis.Oxidative stress is considered...Tendinopathy is a common and complex musculoskeletal disorder,unfortunately current clinical strategies for tendinopathy have low therapeutic efficacy because of complicated pathogenesis.Oxidative stress is considered as the major cause of tendinopathy as well as the important target,but still lacking ideal antioxidant solution.To this end,an efficient reactive oxygen species(ROS)biocatalyst,PtIrRuRhCu high-entropy alloy nanozyme(HEANZ),has been designed for treatment of tendinopathy.The non-ionic block copolymer(polyvinyl pyrrolidone)coated PtIrRuRhCu HEANZ with size of~4.0 nm exhibits good biocompatibility and multiple enzyme-like antioxidant activity(including peroxidase,catalase and superoxide dismutase(SOD)-like)to modulate ROS.The therapeutic efficacy of PtIrRuRhCu HEANZ in tendinopathy has been systematically demonstrated in vitro and in vivo.PtIrRuRhCu HEANZ can alleviate the t-Butyl hydroperoxide(TBHP)stimulated tendinopathy by clearing ROS,reducing inflammation and restoring mitochondrial autophagy.Using phosphoglycerate mutase family member 5(PGAM5)siRNA and FUN14 domain containing protein 1(FUNDC1)siRNA for intervention,we clearly revealed that PtIrRuRhCu HEANZ promots mitochondrial autophagy through upregulating the PGAM5/FUNDC1/glutathione peroxidase 4(GPX4)axis.This study provides a nanozyme strategy for the antioxidant treatment of tendinopathy and provides insights into the therapeutic mechanism.展开更多
Esophageal squamous cell carcinoma (ESCC), as the main histological type of esophageal cancer (EC), has the characteristics of high malignant degree, high mortality and tendency to lymph node metastasis. Despite the c...Esophageal squamous cell carcinoma (ESCC), as the main histological type of esophageal cancer (EC), has the characteristics of high malignant degree, high mortality and tendency to lymph node metastasis. Despite the combination of surgery and chemoradiotherapy, ECSS has a poor prognosis. Ferroptosis is a newly discovered iron-dependent programmed cell death pattern characterized by the accumulation of lipid peroxidation and characteristic morphological changes of mitochondria. It regulates the growth and invasion of cancer cells in various tumors such as gastric cancer and pancreatic cancer. In this article, we mainly introduce the ferroptosis regulatory mechanism in ESCC, hoping to provide a new direction and ideas for the treatment of ECSS.展开更多
基金supported by the National Natural Science Foundation of China(82270386,82070252,and 8207025)the Zhejiang Provincial Medical and Health Science and Technology Plan(2023RC020)the Zhejiang Provincial Natural Science Foundation(LR21H020001).
文摘Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.
基金funded by the National Natural Science Foundation of China(82000042,81870029)Beijing Municipal Natural Science Foundation(7204247)+3 种基金Capital’s Funds for Health Improvement and Research(grant number:2024-2-1101)Start-up Project of Beijing Friendship Hospital,Capital Medical University(Beijing,China)(yyqdktzx2020-3)Key Clinical Specialty Construction Program of Beijing(2020-2022)Research Fund of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital(24QNPY034).
文摘Objective This study investigated the effect of reducing soluble epoxide hydrolase(sEH,encoded by the Ephx2 gene)on the mediation of EETs metabolism during ferroptosis in emphysema in vivo.Methods Male C57BL/6J wild-type(WT)and Ephx2^(-/-)mice received whole-body exposure to either cigarette smoke(CS)or air for 16 weeks.The alveolar structure,pulmonary function,lung tissue morphology,cell death,and ferroptosis levels were assessed following exposure.Results CS exposure caused emphysema,reduced pulmonary function,and induced ferroptosis in mice compared with exposure to air.In contrast,following CS exposure,Ephx2^(-/-)mice exhibited significantly lower levels of emphysema,impaired lung function,lung cell death,intracellular iron,lipid reactive oxygen species,cyclooxygenase-2,4-hydroxynonenal,and malondialdehyde levels than those of WT mice.However,Ephx2^(-/-)mice exhibited higher levels of glutathione and ferritin heavy chain 1 than those of WT mice.SLC7A11 expression was significantly reduced,whereas glutathione peroxidase 4 expression was markedly increased in Ephx2^(-/-)mice compared with WT mice.Statistically significant differences(P<0.05)were observed.Conclusion These results suggest that Ephx2 deficiency inhibits ferroptosis to alleviate CS-induced emphysema,primarily by mitigating its inhibitory effect on the cystine/glutathione/glutathione peroxidase 4 axis.Therefore,Ephx2 represents an effective therapeutic target in CS-induced chronic obstructive pulmonary disease(COPD).
基金supported by the National Natural Science Foundation of China(Grant Number 82373399,52303085)the Science and Tech-nology Development Program of Jilin Province(Grant Number 202302001)Special Project from MOST of China.Thanks to Min-gjie Chen(Shanghai NewCore Biotechnology Co.,Ltd.)for providing data analysis and visualization support.
文摘As one of the key targets of tumor metabolic therapy,glucose dyshomeostasis by disrupting glucose metabolism possesses the potential to reverse therapeutic resistance of a variety of regulated cell deaths(RCDs),but the functional pathways are not fully revealed and employed.Herein,we demonstrate that the intervention on SLC7A11/GSH/GPX4 antioxidant axis by glucose dyshomeostasis can simultaneously promote disulfidptosis,cuproptosis and ferroptosis,which is verified by employing glucose oxidase(GOx)-modified copper-apigenin(CuAp)network nanoshuttles(CuAp@GOx NSs)in ovarian tumor therapy.Ap and GOx can jointly induce glucose dyshomeostasis respectively by inhibiting glucose transporter 1-mediated glucose uptake upstream,and consuming massive glucose downstream.As a result of glucose dyshomeostasis,the NADPH supplement is downregulated,which further disrupts SLC7A11/GSH/GPX4 antioxidant axis.This simultaneously boosts disulfidptosis by facilitating cystine accumulation,cuproptosis by attenuating GSH-mediated Cu+inactivation,and ferroptosis by downregulating GPX4 expression.Owing to the combination of disulfidptosis,cuproptosis and ferroptosis,CuAp@GOx NSs exhibit good efficacy in treating ovarian tumor model.This work proposes an alternative strategy for tumor therapy based on glucose dyshomeostasis,which mainly targets the RCDs relating to SLC7A11/GSH/GPX4 axis.
基金supported by the National Major Research plan of NSFC(No.92368201)the National Key Research and Development Program of China(No.2021YFA1201404)+2 种基金Major Project of the National Natural Science Foundation of China(No.81991514)Jiangsu Province Medical Innovation Center of Orthopedic Surgery(No.CXZX202214)Jiangsu Provincial Key Medical Center Foundation,Jiangsu Provincial Medical Outstanding Talent Foundation,Jiangsu Provincial Medical Youth Talent Foundation and Jiangsu Provincial Key Medical Talent Foundation,and the Fundamental Research Funds for the Central Universities(Nos.14380493,and 14380494).
文摘Tendinopathy is a common and complex musculoskeletal disorder,unfortunately current clinical strategies for tendinopathy have low therapeutic efficacy because of complicated pathogenesis.Oxidative stress is considered as the major cause of tendinopathy as well as the important target,but still lacking ideal antioxidant solution.To this end,an efficient reactive oxygen species(ROS)biocatalyst,PtIrRuRhCu high-entropy alloy nanozyme(HEANZ),has been designed for treatment of tendinopathy.The non-ionic block copolymer(polyvinyl pyrrolidone)coated PtIrRuRhCu HEANZ with size of~4.0 nm exhibits good biocompatibility and multiple enzyme-like antioxidant activity(including peroxidase,catalase and superoxide dismutase(SOD)-like)to modulate ROS.The therapeutic efficacy of PtIrRuRhCu HEANZ in tendinopathy has been systematically demonstrated in vitro and in vivo.PtIrRuRhCu HEANZ can alleviate the t-Butyl hydroperoxide(TBHP)stimulated tendinopathy by clearing ROS,reducing inflammation and restoring mitochondrial autophagy.Using phosphoglycerate mutase family member 5(PGAM5)siRNA and FUN14 domain containing protein 1(FUNDC1)siRNA for intervention,we clearly revealed that PtIrRuRhCu HEANZ promots mitochondrial autophagy through upregulating the PGAM5/FUNDC1/glutathione peroxidase 4(GPX4)axis.This study provides a nanozyme strategy for the antioxidant treatment of tendinopathy and provides insights into the therapeutic mechanism.
文摘Esophageal squamous cell carcinoma (ESCC), as the main histological type of esophageal cancer (EC), has the characteristics of high malignant degree, high mortality and tendency to lymph node metastasis. Despite the combination of surgery and chemoradiotherapy, ECSS has a poor prognosis. Ferroptosis is a newly discovered iron-dependent programmed cell death pattern characterized by the accumulation of lipid peroxidation and characteristic morphological changes of mitochondria. It regulates the growth and invasion of cancer cells in various tumors such as gastric cancer and pancreatic cancer. In this article, we mainly introduce the ferroptosis regulatory mechanism in ESCC, hoping to provide a new direction and ideas for the treatment of ECSS.
