ReferenceID 4927
(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis
Cell Death Dis
Drug-induced liver injury is the major cause of acute liver failure. However, the underlying mechanisms seem to be multifaceted and remain poorly understood, resulting in few effective therapies. Here, we report a novel
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Record Fields
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- Reference Id
- 4927
- Evidence Id
- 21517
- Core Evidence Id
- 21517
- Source Reference Id
- 3110
- Herb2 Reference Id
- HBREF003907
- Subject Paper Key
- HBIN021039_32951003
- Pubmed Id
- 32951003
- Doi
- 10.1038/s41419-020-02961-5
- Paper Title
- (+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis
- Paper Abstract
- Drug-induced liver injury is the major cause of acute liver failure. However, the underlying mechanisms seem to be multifaceted and remain poorly understood, resulting in few effective therapies. Here, we report a novel mechanism that contributes to acetaminophen-induced hepatotoxicity through the induction of ferroptosis, a distinctive form of programmed cell death. We subsequently identified therapies protective against acetaminophen-induced liver damage and found that (+)-clausenamide ((+)-CLA), an active alkaloid isolated from the leaves of Clausena lansium (Lour.) Skeels, inhibited acetaminophen-induced hepatocyte ferroptosis both in vivo and in vitro. Consistently, (+)-CLA significantly alleviated acetaminophen-induced or erastin-induced hepatic pathological damages, hepatic dysfunctions and excessive production of lipid peroxidation both in cultured hepatic cell lines and mouse liver. Furthermore, treatment with (+)-CLA reduced the mRNA level of prostaglandin endoperoxide synthase 2 while it increased the protein level of glutathione peroxidase 4 in hepatocytes and mouse liver, confirming that the inhibition of ferroptosis contributes to the protective effect of (+)-CLA on drug-induced liver damage. We further revealed that (+)-CLA specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability, thereby leading to the activation of the Keap1-Nrf2 pathway to prevent drug-induced hepatocyte ferroptosis. Our studies illustrate the innovative mechanisms of acetaminophen-induced liver damage and present a novel intervention strategy to treat drug overdose by using (+)-CLA.
- Journal
- Cell Death Dis
- Publish Year
- 2020
- Experiment Subject
- mouse; cultured hepatic cell lines
- Experiment Type
- Animal Experiment
- Phenotype Related
- Ferroptosis; Drug-induced Liver Injury; Acute Liver Failure; Acetaminophen-induced Liver Damage; Hepatic Dysfunctions
- Paper Title Cn
- Paper Title En
- (+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis
- Bilingual Status
- semi_complete