<i>Arid1a</i> Deficiency Drives Aristolochic Acid‐Induced Liver Tumorigenesis through <i>Ctnnb1</i> Mutation and Defective Nucleotide Excision Repair

ARID1A, which encodes an important subunit of SWI/SNF complex, is frequently mutated in non-malignant tissues and tumors. However, how ARID1A loss enables environmental carcinogens to initiate tumorigenesis remains unknown. Here, liver-specific Arid1a-deficient (Arid1a^LKO) mice are exposed to aristolochic acid I (AAI), a potent herbal carcinogen. Notably, AAI dramatically accelerated hepatocarcinogenesis in Arid1a-deficient livers, accompanied by a specific 3' splice-site mutation in Ctnnb1 in most tumors and adjacent non-tumorous tissues. This mutation results in exon 3 skipping and subsequent β-catenin activation. Single-nucleus RNA-seq coupled with phylogenetic analyses reveals AAI-induced tumor microenvironment alteration and clonal expansion of β-catenin-activated cells. Conversely, inhibition of β-catenin signaling significantly suppresses AAI-induced tumors in the context of Arid1a loss. Mechanistically, Arid1a deficiency transcriptionally represses the expression of critical genes related to nucleotide excision repair, which removes AAI-derived DNA adducts, due to SWI/SNF complex dysfunction. Simultaneously, it upregulates Nqo1, a key enzyme enhancing AAI bioactivation and AAI-DNA adduct formation. This dual-hit mechanism, characterized by impaired DNA repair and heightened genotoxicity, explains synergistic carcinogenesis. The study unveils ARID1A as a guardian against environmental carcinogens and proposes β-catenin blockade for precision prevention in high-risk patients with ARID1A-mutant benign liver diseases.