PPARα activation attenuates neobavaisoflavone-induced hepatotoxicity by modulating metabolic disorder and oxidative stress.

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.