Comparative transcriptomic analysis reveals STAT3 as a candidate gene involved in aristolochic acid I-induced hepatorenal toxicity.

Aristolochic acids, such as Aristolochic acid I (AAI), are widely recognized for their nephrotoxicity and potential to cause hepatocellular carcinoma. Although previous studies have demonstrated the ability of AAI to induce hepatorenal toxicity, the precise underlying mechanism remains unclear. The objective of this research is to investigate the mechanisms by which AAI induces hepatorenal toxicity. Both in vivo and in vitro studies were conducted, involving the administration of AAI to C57BL/6 mice and the exposure of human hepatocytes (HL-7702/L-02) and proximal kidney tubular epithelial cell (HK-2) to AAI. RNA sequencing analysis of liver and kidney was conducted to ascertain hepatorenal toxicity mechanism, with follow-up experiments for validation. Upon identifying the common target, STAT3, for AAI induced hepatorenal toxicity, we further employed STAT3 inhibitor, Stattic for in vitro validation. The results revealed that elevated expressions of STAT3 caused hepatorenal toxicity, leading to impaired liver and kidney functions, as well as tissue damage. Western Blot demonstrated that AAI increased STAT3 phosphorylation. Furthermore, the application of the STAT3 inhibitor reduced damage to hepatocytes and kidney tubular epithelial cell, confirming the effectiveness of Stattic against AAI-induced harm. These findings provide evidence of the significant hepatorenal toxicity of AAI and indicate that STAT3 may serve as a potential common target.