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PPARα activation attenuates neobavaisoflavone-induced hepatotoxicity by modulating metabolic disorder and oxidative
Jingcheng Zhao1, Wen Wang2, Chenglong Sun3
1Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui province key laboratory of tumor immune microenvironment and immunotherapy, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Uygur Medical Hospital of Xinjiang Uygur Autonomous Region (The Second People's Hospital of Xinjiang Uygur Autonomous Region), Ürümqi, China; Xinjiang Key Laboratory of Evidence-Based and Translation, Hospital Preparation of Traditional Chinese Medicine, Ürümqi 830049, China; Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy, Shihezi University, Shihezi 832002, China.
Introduction:
Neobavaisoflavone (Neo), a major bioactive compound in Psoralea corylifolia L., exhibits potent antibacterial, anti-inflammatory, anticancer, and antioxidant activities; however, the clinical use of P. corylifolia is limited by its potential hepatotoxicity.
Objective:
This study aims to systematically elucidate the hepatotoxic effects of Neo, unravel its underlying molecular mechanisms, and explore potential strategies for prevention and therapeutic intervention.
Methods:
In this study, a multi-model experimental strategy-including zebrafish larvae, high-fat diet (HFD)-fed mice, primary mouse hepatocytes, and human hepatocyte cell lines-was employed to investigate Neo-induced hepatic steatosis. Subsequently, the hepatotoxicity effects and molecular mechanisms of Neo's hepatotoxicity were investigated by ex vivo and in vivo experiments such as Mass spectrometry imaging (MSI), untargeted lipidomic, Transcriptomic analysis, co-immunoprecipitation and crystallographic.
Results:
MSI revealed conserved hepatic accumulation of Neo and its lipid metabolites in both zebrafish and mouse models, with marked deposition of long-chain fatty acids (LCFAs). These findings were corroborated by untargeted lipidomic. Transcriptomic analysis further implicated disruptions in PPARα-mediated fatty acid metabolism and oxidative stress pathways. Mechanistically, co-immunoprecipitation and crystallographic studies demonstrated that Neo binds to the ligand-binding domain of PPARα, specifically at residues Ala333, Tyr334, Met220, Asn219, and Glu286, thereby impairing its nuclear translocation. Importantly, PPARα overexpression or pharmacological activation with fenofibrate (Tricor) significantly attenuated Neo-induced hepatic steatosis and oxidative stress.
Conclusions:
Collectively, these findings uncover a novel mechanism whereby Neo disrupts lipid homeostasis and induces oxidative stress via PPARα inhibition, and highlight PPARα activation as a potential strategy to mitigate Neo-associated hepatotoxicity, offering valuable insights for its safer therapeutic application.
Insights
Neobavaisoflavone (Neo) causes liver injury by inhibiting PPARα, disrupting lipid metabolism and increasing oxidative stress. Activating PPARα can prevent Neo-induced liver damage, enabling safer use of this compound.
Area of Science:
- Pharmacology
- Hepatology
- Molecular Biology
Background:
- Neobavaisoflavone (Neo), a Psoralea corylifolia L. compound, has beneficial activities but poses risks of liver toxicity.
- Understanding Neo's hepatotoxicity is crucial for its clinical application.
Purpose of the Study:
- To investigate the mechanisms of Neo-induced liver injury.
- To explore strategies for mitigating Neo's hepatotoxicity.
Main Methods:
- Multi-model approach using zebrafish, mice, and human/mouse hepatocytes.
- Investigated Neo-induced hepatic steatosis using Mass Spectrometry Imaging (MSI), lipidomics, transcriptomics, co-immunoprecipitation, and crystallography.
Main Results:
- Neo accumulates in the liver, leading to hepatic steatosis and deposition of long-chain fatty acids (LCFAs).
- Neo inhibits PPARα by binding to its ligand-binding domain, impairing nuclear translocation and disrupting fatty acid metabolism and oxidative stress pathways.
- PPARα activation (overexpression or fenofibrate) protected against Neo-induced liver injury.
Conclusions:
- Neo induces liver toxicity by inhibiting PPARα, disrupting lipid homeostasis, and causing oxidative stress.
- PPARα activation is a promising strategy to mitigate Neobavaisoflavone-associated hepatotoxicity.
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