Whether aristolochic acid directly drives hepatocarcinogenesis: comprehensive investigations from mutational signatures to animal models.

Aristolochic Acid (AA) is a class of naturally occurring compounds characterized by potent genotoxicity and carcinogenicity, predominantly found in plants of the Aristolochia genus. The 1993 Belgian weight-loss incident and subsequent research unequivocally established the association between AA and "Aristolochic Acid Nephropathy" (AAN) as well as Balkan Endemic Nephropathy (BEN), prompting global regulatory actions. AA undergoes nitroreduction to generate highly reactive intermediates, which form persistent DNA adducts, inducing A:T to T:A transversion mutations during DNA replication. In 2017, 78% (76/98) of hepatocellular carcinoma (HCC) samples collected from two Taiwanese hospitals exhibited the characteristic mutational signature COSMIC SBS22, sparking a global debate on whether AA contributes to liver carcinogenesis. This review systematically synthesizes the research progress on AA, encompassing its historical applications, metabolic mechanisms, genotoxic features, and its potential causal relationship with HCC. It highlights the necessity of employing multi-omics technologies to elucidate the regulatory networks of AA-metabolizing enzymes, developing non-invasive biomarkers, and rigorously validating carcinogenic mechanisms through animal models. Furthermore, strengthening the regulation of AA-containing herbal medicines and enhancing global exposure surveillance are imperative for mitigating the burden of liver cancer. This review provides a comprehensive perspective on the toxicological mechanisms and carcinogenic risks of AA, offering insights into precision prevention and intervention strategies.