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HMGB1 inhibition blocks ferroptosis and oxidative stress to ameliorate sepsis‐induced acute lung injury by activating the Nrf2 pathway
- Source :
- Kaohsiung Journal of Medical Sciences, Vol 40, Iss 8, Pp 710-721 (2024)
- Publication Year :
- 2024
- Publisher :
- Wiley, 2024.
-
Abstract
- Abstract The proinflammatory properties of high‐mobility group box protein 1 (HMGB1) in sepsis have been extensively studied. This study aimed to investigate the impact of HMGB1 on ferroptosis and its molecular mechanism in sepsis‐induced acute lung injury (ALI). A septic mouse model was established using the cecal ligation and puncture method. Blocking HMGB1 resulted in improved survival rates, reduced lung injury, decreased levels of ferroptosis markers (reactive oxygen species, malondialdehyde, and Fe2+), and enhanced antioxidant enzyme activities (superoxide dismutase and catalase) in septic mice. In addition, knockdown of HMGB1 reduced cellular permeability, ferroptosis markers, and raised antioxidant enzyme levels in lipopolysaccharide (LPS)‐stimulated MLE‐12 cells. Silencing of HMGB1 led to elevations in the expressions of ferroptosis core‐regulators in LPS‐treated MLE‐12 cells, such as solute carrier family 7 member 11 (SLC7A11), solute carrier family 3 member A2 (SLC3A2), and glutathione peroxidase 4. Furthermore, blocking HMGB1 did not alter ferroptosis, oxidative stress‐related changes, and permeability in LPS‐treated MLE‐12 cells that were pretreated with ferrostatin‐1 (a ferroptosis inhibitor). HMGB1 inhibition also led to elevated expressions of nuclear factor erythroid 2‐related factor 2 (Nrf2) and its downstream targets, heme oxygenase‐1 (HO‐1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) in LPS‐treated MLE‐12 cells and lung tissues from septic mice. The Nrf2‐specific inhibitor ML385 reversed the effects of HMGB1 silencing on ferroptosis and cell permeability in LPS‐treated MLE‐12 cells. Our findings indicated that the inhibition of HMGB1 restrains ferroptosis and oxidative stress, thereby alleviating sepsis‐induced ALI through the activation of Nrf2 signaling.
- Subjects :
- acute lung injury
ferroptosis
HMGB1
Nrf2
sepsis
Medicine (General)
R5-920
Subjects
Details
- Language :
- English
- ISSN :
- 24108650 and 1607551X
- Volume :
- 40
- Issue :
- 8
- Database :
- Directory of Open Access Journals
- Journal :
- Kaohsiung Journal of Medical Sciences
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.bb296f359c7e4ded980f3f0e15085a72
- Document Type :
- article
- Full Text :
- https://doi.org/10.1002/kjm2.12851