Bio: Dr. Yang Luan studies genetic toxicology, investigating genotoxic mechanisms of environmental pollutants and herbal toxins using in vivo/in vitro models (DNA damage, chromosomal aberrations, gene mutations). They develop novel assays (error-corrected NGS, microfluidics) and human blood biomarkers (PIG-A) for carcinogenic risk prediction.

Abstract: Aristolochic acid I (AAI) is a potent carcinogen linked to upper tract urothelial carcinoma (UTUC) and liver cancer, though its mechanisms remain unclear [1]. We hypothesized that inflammatory conditions enhance the hepatocarcinogenicity of AAI. Given the increasing prevalence of metabolic dysfunction-associated steatohepatitis (MASH), we designed our study to investigate AAI's mutagenicity under steatohepatitis inflammation using mouse models and human induced hepatocytes (hiHeps). We combined DNA adduct quantification with PECC-seq (error-corrected NGS) [2] for mutation signatures. In hiHeps, AAI generated DNA adducts, which could be reversed by ascorbate, confirming the involvement of AAI free radicals as active intermediates [3]. MASH livers showed slightly reduced AAI-DNA adducts versus controls, suggesting antioxidant adaptation. However, mutation analysis revealed a 6-fold higher TA→AT mutation rate, indicating the mutagenic potential of AAI remains significant in the context of MASH inflammation. Trinucleotide signatures revealed dual mechanisms–direct AAI-adduct mutations (A:T→T:A) and ROS-mediated G:C→A:T mutations. Those findings highlight inflammation's pivotal role–it creates a pro-carcinogenic microenvironment through: (i) compensatory proliferation increasing mutation fixation, and (ii) background oxidative stress synergizing with AAI-induced damage. Our study establishes that inflammation transforms AAI from a latent hepatotoxin to a potent carcinogen, explaining its conditional liver cancer risk.

Reference:

1. NG A W T, POON S L, HUANG M N, et al. Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia [J]. Sci Transl Med, 2017, 9(412): 12.

2. YOU X, CAO Y, SUZUKI T, et al. Genome-wide direct quantification of in vivo mutagenesis using high-accuracy paired-end and complementary consensus sequencing [J]. Nucleic Acids Res, 2023, 51(21).

3. LI P-L, HUANG C-H, MAO L, et al. An unprecedented free radical mechanism for the formation of DNA adducts by the carcinogenic N-sulfonated metabolite of aristolochic acids [J]. Free Radical Biology and Medicine, 2023, 205: 332-45.