Aristolochic Acid and Hepatocellular Carcinoma: A Critical Review of Genotoxic and Inflammatory Mechanisms.

Aristolochic acid (AA), a naturally occurring compound found in Aristolochia plants, is a well-established nephrotoxin and Group 1 carcinogen. Emerging evidence suggests a potential link between AA exposure and hepatocellular carcinoma (HCC), one of the leading causes of cancer-related mortality worldwide. This review critically evaluates current knowledge on AA's hepatic metabolism, its formation of persistent DNA adducts, and the induction of inflammatory responses in the liver. Based on preclinical and indirect human evidence, we propose a working hypothesis that AA may contribute to hepatocarcinogenesis through a dual mechanism: genotoxic (primarily via H-ras and p53 mutations resulting from AA-DNA adducts) and non-genotoxic (via chronic inflammation involving IL-6, TNF-α, and NF-κB activation, as well as epithelial-mesenchymal transition). We note, however, that these mechanisms remain to be validated in human cohorts and do not yet establish causality. Recent studies have identified novel mechanisms, including PDK4-mediated mitochondrial dysfunction, ferroptosis inhibition via p53 hijacking, and ARID1A deficiency as a susceptibility factor. A recent meta-analysis quantified a significantly increased risk of liver cancer following AA exposure in epidemiological studies. While direct causal evidence in humans remains limited, the high mutational burden observed in AA-exposed liver tissues warrants caution. Nevertheless, the primary public health priority pertains to the prevention of AA exposure. Further epidemiological and mechanistic studies are urgently needed.