SIRT5‐mediated HOXA5 desuccinylation inhibits ferroptosis to alleviate sepsis induced‐lung injury
Abstract Acute lung injury (ALI) is a common and severe complication of sepsis with a high mortality rate. Ferroptosis, an iron‐dependent form of cell death, contributes to lung injury. Homeobox A5 (HOXA5) is involved in the regulation of septic acute kidney damage; however, its function on ferropto...
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Wiley
2025-01-01
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| Series: | Kaohsiung Journal of Medical Sciences |
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| Online Access: | https://doi.org/10.1002/kjm2.12921 |
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| author | Lei Wang Heng Fan Min Sun Ji‐Hui Ye |
| author_facet | Lei Wang Heng Fan Min Sun Ji‐Hui Ye |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | Abstract Acute lung injury (ALI) is a common and severe complication of sepsis with a high mortality rate. Ferroptosis, an iron‐dependent form of cell death, contributes to lung injury. Homeobox A5 (HOXA5) is involved in the regulation of septic acute kidney damage; however, its function on ferroptosis in septic ALI remains unclear. An in vitro model of septic lung injury was established in the pulmonary epithelial cell line (MLE‐12) via lipopolysaccharide (LPS) stimulation. Cell viability, ferrous iron (Fe2+) level, and cellular lipid reactive oxygen species (ROS) were determined with Cell Counting Kit‐8 assay, iron assay kit, and BODIPY™ 665/676 molecular probe, respectively. HOXA5, ferroptosis suppressor protein 1 (FSP1), sirtuin 5 (SIRT5), and glutathione peroxidase 4 (GPX4) expressions were measured using western blotting and Real‐Time Quantitative Polymerase Chain Reaction (RT‐qPCR. Chromatin immunoprecipitation and luciferase reporter assays were performed to validate HOXA5 binding to the FSP1/GPX4 promoter, and regulation of SIRT5 on HOXA5 desuccinylation was confirmed through co‐immunoprecipitation. LPS stimulation induced ferroptosis (reduced cell viability, elevated Fe2+ and lipid ROS levels, and decreased GPX4 levels) and downregulated FSP1 and HOXA5 protein levels. HOXA5 overexpression neutralized LPS‐induced ferroptosis. Moreover, LPS exposure inhibited HOXA5 binding to the FSP1 promoter, which was counteracted via HOXA5 overexpression. Furthermore, SIRT5 overexpression suppressed LPS‐induced ferroptosis. In LPS‐challenged MLE‐12 cells, SIRT5‐mediated HOXA5 desuccinylation was reduced. HOXA5 depletion neutralized the suppressive role of SIRT5 overexpression in LPS‐induced ferroptosis. SIRT5‐mediated HOXA5 desuccinylation inhibited LPS‐induced ferroptosis by upregulating FSP1, which may offer a prospective therapeutic strategy for septic lung injury. |
| format | Article |
| id | doaj-art-5e4eb69aef4a455f928b10faa397cfd6 |
| institution | Kabale University |
| issn | 1607-551X 2410-8650 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Kaohsiung Journal of Medical Sciences |
| spelling | doaj-art-5e4eb69aef4a455f928b10faa397cfd62025-01-11T05:35:55ZengWileyKaohsiung Journal of Medical Sciences1607-551X2410-86502025-01-01411n/an/a10.1002/kjm2.12921SIRT5‐mediated HOXA5 desuccinylation inhibits ferroptosis to alleviate sepsis induced‐lung injuryLei Wang0Heng Fan1Min Sun2Ji‐Hui Ye3Department of Critical Care Medicine The First Affiliated Hospital of Ningbo University Ningbo Zhejiang ChinaDepartment of Critical Care Medicine The First Affiliated Hospital of Ningbo University Ningbo Zhejiang ChinaDepartment of Critical Care Medicine The First Affiliated Hospital of Ningbo University Ningbo Zhejiang ChinaDepartment of Critical Care Medicine The First Affiliated Hospital of Ningbo University Ningbo Zhejiang ChinaAbstract Acute lung injury (ALI) is a common and severe complication of sepsis with a high mortality rate. Ferroptosis, an iron‐dependent form of cell death, contributes to lung injury. Homeobox A5 (HOXA5) is involved in the regulation of septic acute kidney damage; however, its function on ferroptosis in septic ALI remains unclear. An in vitro model of septic lung injury was established in the pulmonary epithelial cell line (MLE‐12) via lipopolysaccharide (LPS) stimulation. Cell viability, ferrous iron (Fe2+) level, and cellular lipid reactive oxygen species (ROS) were determined with Cell Counting Kit‐8 assay, iron assay kit, and BODIPY™ 665/676 molecular probe, respectively. HOXA5, ferroptosis suppressor protein 1 (FSP1), sirtuin 5 (SIRT5), and glutathione peroxidase 4 (GPX4) expressions were measured using western blotting and Real‐Time Quantitative Polymerase Chain Reaction (RT‐qPCR. Chromatin immunoprecipitation and luciferase reporter assays were performed to validate HOXA5 binding to the FSP1/GPX4 promoter, and regulation of SIRT5 on HOXA5 desuccinylation was confirmed through co‐immunoprecipitation. LPS stimulation induced ferroptosis (reduced cell viability, elevated Fe2+ and lipid ROS levels, and decreased GPX4 levels) and downregulated FSP1 and HOXA5 protein levels. HOXA5 overexpression neutralized LPS‐induced ferroptosis. Moreover, LPS exposure inhibited HOXA5 binding to the FSP1 promoter, which was counteracted via HOXA5 overexpression. Furthermore, SIRT5 overexpression suppressed LPS‐induced ferroptosis. In LPS‐challenged MLE‐12 cells, SIRT5‐mediated HOXA5 desuccinylation was reduced. HOXA5 depletion neutralized the suppressive role of SIRT5 overexpression in LPS‐induced ferroptosis. SIRT5‐mediated HOXA5 desuccinylation inhibited LPS‐induced ferroptosis by upregulating FSP1, which may offer a prospective therapeutic strategy for septic lung injury.https://doi.org/10.1002/kjm2.12921desuccinylationferroptosisHOXA5sepsis‐induced lung injurySIRT5 |
| spellingShingle | Lei Wang Heng Fan Min Sun Ji‐Hui Ye SIRT5‐mediated HOXA5 desuccinylation inhibits ferroptosis to alleviate sepsis induced‐lung injury Kaohsiung Journal of Medical Sciences desuccinylation ferroptosis HOXA5 sepsis‐induced lung injury SIRT5 |
| title | SIRT5‐mediated HOXA5 desuccinylation inhibits ferroptosis to alleviate sepsis induced‐lung injury |
| title_full | SIRT5‐mediated HOXA5 desuccinylation inhibits ferroptosis to alleviate sepsis induced‐lung injury |
| title_fullStr | SIRT5‐mediated HOXA5 desuccinylation inhibits ferroptosis to alleviate sepsis induced‐lung injury |
| title_full_unstemmed | SIRT5‐mediated HOXA5 desuccinylation inhibits ferroptosis to alleviate sepsis induced‐lung injury |
| title_short | SIRT5‐mediated HOXA5 desuccinylation inhibits ferroptosis to alleviate sepsis induced‐lung injury |
| title_sort | sirt5 mediated hoxa5 desuccinylation inhibits ferroptosis to alleviate sepsis induced lung injury |
| topic | desuccinylation ferroptosis HOXA5 sepsis‐induced lung injury SIRT5 |
| url | https://doi.org/10.1002/kjm2.12921 |
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