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
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.
