EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury
Abstract Sepsis-associated acute liver injury (SALI) is a major clinical complication of sepsis due to excessive, unfettered inflammation. In recent years, the role of epigenetic regulatory mechanisms in SALI has been gradually emphasized. Here, we investigated the effects of a Histone-lysine N-meth...
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| Language: | English |
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BMC
2025-06-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-025-01892-2 |
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| author | Meihua Mei Ying You Ningxin Tan Xiaoshun He Junqi Huang |
| author_facet | Meihua Mei Ying You Ningxin Tan Xiaoshun He Junqi Huang |
| author_sort | Meihua Mei |
| collection | DOAJ |
| description | Abstract Sepsis-associated acute liver injury (SALI) is a major clinical complication of sepsis due to excessive, unfettered inflammation. In recent years, the role of epigenetic regulatory mechanisms in SALI has been gradually emphasized. Here, we investigated the effects of a Histone-lysine N-methyltransferase EZH1 (Enhancer of zeste homolog 1) inhibition on promoting ferroptosis resistance to activate nuclear factor, erythroid derived 2, like 2 (NRF2) in SALI. We found that EZH1 deficiency improved animal survival in lethal sepsis. EZH1 deficiency mice exhibited alleviated SALI with decreased hepatocellular ferroptosis. EZH1 deficiency attenuated the H3K27me3 modification in the Nfe2l2 promoter, lending to the increased expression and nuclear translocation of NRF2. In the in vitro, LPS-induced ferroptosis model, EZH1 inhibitor DS3201 exhibited an anti-ferroptosis effect, which was reversed NRF2 inhibitor ML385. These findings indicate that EZH1 deficiency or inhibition with DS3201 alleviates ferroptosis in the liver by activating the NRF2, and it is suggested that targeting EZH1 may be a new therapeutic strategy in SALI. Graphical abstract |
| format | Article |
| id | doaj-art-1028960d4a7f43e985f9f5657d720e3f |
| institution | DOAJ |
| issn | 1868-7083 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj-art-1028960d4a7f43e985f9f5657d720e3f2025-08-20T03:21:03ZengBMCClinical Epigenetics1868-70832025-06-0117111610.1186/s13148-025-01892-2EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injuryMeihua Mei0Ying You1Ningxin Tan2Xiaoshun He3Junqi Huang4Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-Sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-Sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-Sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-Sen UniversityAbstract Sepsis-associated acute liver injury (SALI) is a major clinical complication of sepsis due to excessive, unfettered inflammation. In recent years, the role of epigenetic regulatory mechanisms in SALI has been gradually emphasized. Here, we investigated the effects of a Histone-lysine N-methyltransferase EZH1 (Enhancer of zeste homolog 1) inhibition on promoting ferroptosis resistance to activate nuclear factor, erythroid derived 2, like 2 (NRF2) in SALI. We found that EZH1 deficiency improved animal survival in lethal sepsis. EZH1 deficiency mice exhibited alleviated SALI with decreased hepatocellular ferroptosis. EZH1 deficiency attenuated the H3K27me3 modification in the Nfe2l2 promoter, lending to the increased expression and nuclear translocation of NRF2. In the in vitro, LPS-induced ferroptosis model, EZH1 inhibitor DS3201 exhibited an anti-ferroptosis effect, which was reversed NRF2 inhibitor ML385. These findings indicate that EZH1 deficiency or inhibition with DS3201 alleviates ferroptosis in the liver by activating the NRF2, and it is suggested that targeting EZH1 may be a new therapeutic strategy in SALI. Graphical abstracthttps://doi.org/10.1186/s13148-025-01892-2SepsisLiver injuryEZH1FerroptosisNRF2 |
| spellingShingle | Meihua Mei Ying You Ningxin Tan Xiaoshun He Junqi Huang EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury Clinical Epigenetics Sepsis Liver injury EZH1 Ferroptosis NRF2 |
| title | EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury |
| title_full | EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury |
| title_fullStr | EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury |
| title_full_unstemmed | EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury |
| title_short | EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury |
| title_sort | ezh1 deficiency promotes ferroptosis resistance by activating nrf2 in sepsis associated liver injury |
| topic | Sepsis Liver injury EZH1 Ferroptosis NRF2 |
| url | https://doi.org/10.1186/s13148-025-01892-2 |
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