Mechanisms of aristolochic acid I Hepatotoxicity: Central role of PDK4-Induced mitochondrial dysfunction and hepatic inflammation.

Aristolochic acids are herbal compound found in many traditional medicines. Among these compounds, AAI is the most frequent and the most toxic, and it could accumulate in water or soil to contaminate our foods, inducing severe toxic effects on human health. Previous research has reported AAI was involved in HCC development mainly by T > A mutation induction. HCC is a chronic disease, which developed from severe liver injury and dysfunction. But the effects of AAI on liver function and involved mechanisms is not evident and still needs to be clarified. In our current research, we found AAI treatment induced severe liver injury and dysfunction in vivo and in vitro. Further research showed that AAI exposure induced activation of M1 macrophage-the proinflammatory phenotype, following acute inflammatory responses induction in liver. Additionally, our genome-wide gene expression analyses indicated AAI exposure affects hepatic metabolic function mainly by PDK4 activation, resulting in mitochondrial dysfunction. Further, AAI exposure induced p53 activation and ER stress, following apoptosis induction of hepatocytes. In summary, AAI exposure triggers severe liver dysfunction mainly resulting from M1 macrophage activation-induced inflammatory responses, and PDK4/p53/ER stress axis dependent hepatic apoptosis. Most importantly, this result enriched the mechanisms of AAI-induced toxicity and identified the PDK4 as a molecular clinical marker for HCC precautions.