Low-dose Olaparib improves septic cardiac function by reducing ferroptosis via accelerated mitophagy flux

Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving ferroptosis. Olaparib, a classic targeted drug used in oncology, has demonstrated potential protective effects against sepsis. However, the...

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Bibliographic Details
Published in:Pharmacological research 2024-02, Vol.200, p.107056-107056, Article 107056
Main Authors: Liu, Ruixue, Li, Fengjuan, Hao, Shuai, Hou, Dongyao, Zeng, Xue, Huang, He, Sethi, Gautam, Guo, Jun, Duan, Chenyang
Format: Article
Language:English
Subjects:
Animals
Cardiac function
Ferroptosis
Humans
Mice
Mitophagy
Mitophagy - physiology
Molecular Docking Simulation
Olaparib
Phosphatidate Phosphatase
Phthalazines
Piperazines
Sepsis
Sepsis - physiopathology
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Summary:Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving ferroptosis. Olaparib, a classic targeted drug used in oncology, has demonstrated potential protective effects against sepsis. However, the exact mechanisms underlying its action remain to be elucidated. In our study, we meticulously screened ferroptosis genes associated with sepsis, and conducted comprehensive functional enrichment analyses to delineate the relationship between ferroptosis and mitochondrial damage. Eight sepsis-characterized ferroptosis genes were identified in sepsis patients, including DPP4, LPIN1, PGD, HP, MAPK14, POR, GCLM, and SLC38A1, which were significantly correlated with mitochondrial quality imbalance. Utilizing DrugBank and molecular docking, we demonstrated a robust interaction of Olaparib with these genes. Lipopolysaccharide (LPS)-stimulated HL-1 cells and monocytes were used to establish an in vitro sepsis model. Additionally, an in vivo model was developed using mice subjected to cecal ligation and perforation (CLP). Intriguingly, low-dose Olaparib (5 mg/kg) effectively targeted and mitigated markers associated with ferroptosis, concurrently improving mitochondrial quality. This led to a marked enhancement in cardiac function and a significant increase in survival rates in septic mice (p 
ISSN:1043-6618
1096-1186
DOI:10.1016/j.phrs.2023.107056