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Toosendanin Induces Hepatotoxicity by Facilitating ALOX5-Mediated Lipid Peroxidation and Sensitizing Cells to
Jiajie Ni1, Liru Huang1, Yifan Tian1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Abstract:
Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying mechanisms remain elusive. Methods: HepG2 cells were treated with TSN and analyzed using Western blotting and qPCR assays for related gene transcription and protein expression. Lipid peroxidation and ferroptosis markers were measured. Balb/c and C57BL/6 mice received various doses of TSN administration, and their liver function was assessed with serum biochemistry and histopathology. Network pharmacology and oxidative lipidomics were performed to identify key targets and metabolites. Results: TSN triggered ferroptosis both in vitro and in vivo, accompanied by the elevated expression of 5-lipoxygenase (ALOX5) and its downstream metabolites. The ALOX5 level modulated hepatocyte sensitivity to TSN-induced ferroptotic damage. An ALOX5 knockdown alleviated TSN-induced liver injury and ferroptosis in vivo. Conclusions: Our study demonstrated that TSN induces hepatotoxicity by facilitating ALOX5-mediated lipid peroxidation, thereby sensitizing cells to ferroptosis.
Insights
Toosendanin, a component of traditional Chinese medicine, causes liver damage by triggering ferroptosis, a cell death pathway. This process involves 5-lipoxygenase (ALOX5), highlighting a new mechanism for hepatotoxicity.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used for ascariasis.
- Hepatotoxicity is a limiting factor in FMT application.
- Toosendanin (TSN) is identified as the primary toxic component responsible for FMT-induced liver injury, but its mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism of TSN-induced hepatotoxicity.
- To investigate the role of ferroptosis in TSN-induced liver injury.
- To identify key molecular targets involved in TSN toxicity.
Main Methods:
- In vitro studies using HepG2 cells treated with TSN.
- In vivo studies using Balb/c and C57BL/6 mice.
- Analysis of gene transcription, protein expression, lipid peroxidation, and ferroptosis markers.
- Network pharmacology and oxidative lipidomics approaches.
Main Results:
- TSN exposure induced ferroptosis in hepatocytes and mouse livers.
- Elevated 5-lipoxygenase (ALOX5) expression and its metabolites were observed.
- ALOX5 levels correlated with hepatocyte sensitivity to TSN-induced damage.
- ALOX5 knockdown significantly reduced TSN-induced liver injury and ferroptosis.
Conclusions:
- TSN induces hepatotoxicity by promoting ALOX5-mediated lipid peroxidation.
- This process sensitizes hepatocytes to ferroptosis, leading to liver damage.
- Targeting ALOX5 may offer a therapeutic strategy for TSN-induced hepatotoxicity.
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