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AAs are highly nephrotoxic and carcinogenic, mediated by oxidative stress and bioactivation\u2010induced DNA damage and mutagenicity. Nevertheless, some Lepidoptera, including\n                    <jats:italic>Pachliopta aristolochiae<\/jats:italic>\n                    , feed exclusively on Aristolochiaceae and sequester AAs as a chemical defense. This is uncommon in nature and it is not yet fully understood how these insects avoid the lethal effects of AAs. To address this question, we investigate\n                    <jats:italic>Pac. aristolochiae<\/jats:italic>\n                    \u2019s AA\u2010resistance mechanisms by employing metabolic analyses, multiomics analyses, in situ imaging and more. Our findings indicate that AAs may be detoxified through biotransformation and a robust antioxidant system, involving candidate genes such as 15\u2010oxo\u2010prostaglandin 13\u2010reductases (\n                    <jats:italic>PGRs<\/jats:italic>\n                    ), cytochrome P450s, and catalases. Unexpectedly, DNA adducts, the covalent binding products from activated AA intermediates, are detected across most life stages of\n                    <jats:italic>Pac. aristolochiae<\/jats:italic>\n                    , revealing that\n                    <jats:italic>Pac. aristolochiae<\/jats:italic>\n                    can maintain genomic integrity despite a substantial burden (reaching over 1800 AA\u2010DNA adducts per 10\n                    <jats:sup>8<\/jats:sup>\n                    nucleotides in adults, approximately 1 adduct per 55\u00a0000 nucleotides). Interestingly, however, no detectable DNA adducts are observed in wing discs, a representative organ undergoing metamorphosis, and AAs in testes are confined to somatic but not germ cells. Therefore, the strategies to protect against AA\u2010induced mutagenicity likely include restricted AA distribution in critical tissues and enhanced DNA repair. Using butterflies as an evolutionary model, we identify\n                    <jats:italic>PTGR1<\/jats:italic>\n                    , the human\n                    <jats:italic>PGR<\/jats:italic>\n                    homolog, as a potential target of AA resistance, which is associated with human acute kidney injury. Validation in human cells further demonstrates its role in reducing AA\u2010induced cytotoxicity and lipid peroxidation. Our study highlights insect AA tolerance as a means to discover human protective mechanisms, thereby suggesting new avenues for preventing AA\u2010related diseases.\n                  <\/jats:p>","DOI":"10.1002\/advs.202518072","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T03:31:01Z","timestamp":1767583861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanisms of Aristolochic Acid Resistance in Specialist Butterflies and Evolutionary Insights for Potential Protective Pathways"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2211-7803","authenticated-orcid":false,"given":"Yang","family":"Luan","sequence":"first","affiliation":[{"name":"School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai 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Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM Guizhou Medical University  Guiyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanyuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation Shenyang Pharmaceutical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Shen","sequence":"additional","affiliation":[{"name":"Shimazu (China) Co., Ltd  Shanghai Branch China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiyi","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyue","family":"You","sequence":"additional","affiliation":[{"name":"School of Public 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