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However, how\n                    <jats:italic>ARID1A<\/jats:italic>\n                    loss enables environmental carcinogens to initiate tumorigenesis remains unknown. Here, liver\u2010specific\n                    <jats:italic>Arid1a<\/jats:italic>\n                    \u2010deficient (\n                    <jats:italic>\n                      Arid1a\n                      <jats:sup>LKO<\/jats:sup>\n                    <\/jats:italic>\n                    ) mice are exposed to aristolochic acid I (AAI), a potent herbal carcinogen. Notably, AAI dramatically accelerated hepatocarcinogenesis in\n                    <jats:italic>Arid1a<\/jats:italic>\n                    \u2010deficient livers, accompanied by a specific 3\u2032 splice\u2010site mutation in\n                    <jats:italic>Ctnnb1<\/jats:italic>\n                    in most tumors and adjacent non\u2010tumorous tissues. This mutation results in exon 3 skipping and subsequent \u03b2\u2010catenin activation. Single\u2010nucleus RNA\u2010seq coupled with phylogenetic analyses reveals AAI\u2010induced tumor microenvironment alteration and clonal expansion of \u03b2\u2010catenin\u2010activated cells. Conversely, inhibition of \u03b2\u2010catenin signaling significantly suppresses AAI\u2010induced tumors in the context of\n                    <jats:italic>Arid1a<\/jats:italic>\n                    loss. Mechanistically,\n                    <jats:italic>Arid1a<\/jats:italic>\n                    deficiency transcriptionally represses the expression of critical genes related to nucleotide excision repair, which removes AAI\u2010derived DNA adducts, due to SWI\/SNF complex dysfunction. Simultaneously, it upregulates Nqo1, a key enzyme enhancing AAI bioactivation and AAI\u2010DNA adduct formation. This dual\u2010hit mechanism, characterized by impaired DNA repair and heightened genotoxicity, explains synergistic carcinogenesis. The study unveils ARID1A as a guardian against environmental carcinogens and proposes \u03b2\u2010catenin blockade for precision prevention in high\u2010risk patients with\n                    <jats:italic>ARID1A<\/jats:italic>\n                    \u2010mutant benign liver diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202513981","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T11:46:04Z","timestamp":1761306364000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<i>Arid1a<\/i>\n                    Deficiency Drives Aristolochic Acid\u2010Induced Liver Tumorigenesis through\n                    <i>Ctnnb1<\/i>\n                    Mutation and Defective Nucleotide Excision Repair"],"prefix":"10.1002","volume":"13","author":[{"given":"Lan","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education) and 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