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

Abstract 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.