Aristolochic acid I orchestrates multi-organ carcinogenesis through apoptotic pathway in bladder, kidney, and liver cancers: a multi-omics dissection
Abstract Aristolochic acid I (AA-I), a naturally occurring compound derived from plants of the genus Aristolochia, is a well-documented nephrotoxin and carcinogen linked to bladder (BLCA), kidney (KIRC), and liver (LIHC) cancers. Despite extensive research, the molecular mechanisms underlying AA-I-i...
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SpringerOpen
2025-06-01
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| Series: | Environmental Sciences Europe |
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| Online Access: | https://doi.org/10.1186/s12302-025-01146-1 |
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| author | Bitian Zhang Ping-Chung Leung Chun-Kwok Wong Dongjie Wang |
| author_facet | Bitian Zhang Ping-Chung Leung Chun-Kwok Wong Dongjie Wang |
| author_sort | Bitian Zhang |
| collection | DOAJ |
| description | Abstract Aristolochic acid I (AA-I), a naturally occurring compound derived from plants of the genus Aristolochia, is a well-documented nephrotoxin and carcinogen linked to bladder (BLCA), kidney (KIRC), and liver (LIHC) cancers. Despite extensive research, the molecular mechanisms underlying AA-I-induced carcinogenesis remain incompletely understood. Using in silico multi-omics approaches, we demonstrate that AA-I orchestrates multi-organ carcinogenesis through the rewiring of apoptotic pathways. In BLCA, AA-I modulates apoptotic signaling by targeting key genes, such as ABHD16A, DYRK4, UCHL1, and AHCY, promoting metabolic reprogramming and cell survival. Molecular docking studies reveal direct interactions between AA-I and these proteins, potentially modulating their enzymatic activities. In KIRC, AA-I hijacks apoptotic pathways via mast cells, which emerge as central mediators of immune evasion through ligand–receptor pairs (e.g., MIF–CD74 and CSF1–CSF1R). Mast cells also regulate apoptosis and cell cycle pathways, offering novel therapeutic targets for AA-I-associated renal malignancies. In LIHC, AA-I disrupts apoptotic signaling through oncogenic drivers, such as AGAP9 and WNT8A, while the protective gene SV2C exhibits downregulation in tumors. Our findings highlight the pivotal role of apoptotic pathway dysregulation in AA-I-induced carcinogenesis across multiple cancer types and uncover actionable targets. However, it is important to note that this study is based on the in silico computational analyses, and further experimental validation through in vitro and in vivo studies is necessary to confirm these findings. By elucidating potential targets and mechanisms, this work underscores the need for continued investigation into AA-I's epigenetic impacts and its broader implications for global oncology and public health. Highlights Aristolochic acid I (AA-I) drives tissue-specific oncogenesis through dual mutagenic and non-mutagenic mechanisms Mast cells emerge as key mediators of AA-I-induced immune evasion in kidney cancer AA-I reprograms metabolic and epigenetic networks in bladder cancer Divergent prognostic biomarkers link AA-I exposure to hepatocellular carcinoma outcomes Conserved AA-I interaction networks highlight therapeutic vulnerabilities |
| format | Article |
| id | doaj-art-1e244b5a599f4f47abce817fa52d4f8f |
| institution | DOAJ |
| issn | 2190-4715 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | Environmental Sciences Europe |
| spelling | doaj-art-1e244b5a599f4f47abce817fa52d4f8f2025-08-20T03:21:02ZengSpringerOpenEnvironmental Sciences Europe2190-47152025-06-0137112010.1186/s12302-025-01146-1Aristolochic acid I orchestrates multi-organ carcinogenesis through apoptotic pathway in bladder, kidney, and liver cancers: a multi-omics dissectionBitian Zhang0Ping-Chung Leung1Chun-Kwok Wong2Dongjie Wang3Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong KongInstitute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong KongInstitute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong KongInstitute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong KongAbstract Aristolochic acid I (AA-I), a naturally occurring compound derived from plants of the genus Aristolochia, is a well-documented nephrotoxin and carcinogen linked to bladder (BLCA), kidney (KIRC), and liver (LIHC) cancers. Despite extensive research, the molecular mechanisms underlying AA-I-induced carcinogenesis remain incompletely understood. Using in silico multi-omics approaches, we demonstrate that AA-I orchestrates multi-organ carcinogenesis through the rewiring of apoptotic pathways. In BLCA, AA-I modulates apoptotic signaling by targeting key genes, such as ABHD16A, DYRK4, UCHL1, and AHCY, promoting metabolic reprogramming and cell survival. Molecular docking studies reveal direct interactions between AA-I and these proteins, potentially modulating their enzymatic activities. In KIRC, AA-I hijacks apoptotic pathways via mast cells, which emerge as central mediators of immune evasion through ligand–receptor pairs (e.g., MIF–CD74 and CSF1–CSF1R). Mast cells also regulate apoptosis and cell cycle pathways, offering novel therapeutic targets for AA-I-associated renal malignancies. In LIHC, AA-I disrupts apoptotic signaling through oncogenic drivers, such as AGAP9 and WNT8A, while the protective gene SV2C exhibits downregulation in tumors. Our findings highlight the pivotal role of apoptotic pathway dysregulation in AA-I-induced carcinogenesis across multiple cancer types and uncover actionable targets. However, it is important to note that this study is based on the in silico computational analyses, and further experimental validation through in vitro and in vivo studies is necessary to confirm these findings. By elucidating potential targets and mechanisms, this work underscores the need for continued investigation into AA-I's epigenetic impacts and its broader implications for global oncology and public health. Highlights Aristolochic acid I (AA-I) drives tissue-specific oncogenesis through dual mutagenic and non-mutagenic mechanisms Mast cells emerge as key mediators of AA-I-induced immune evasion in kidney cancer AA-I reprograms metabolic and epigenetic networks in bladder cancer Divergent prognostic biomarkers link AA-I exposure to hepatocellular carcinoma outcomes Conserved AA-I interaction networks highlight therapeutic vulnerabilitieshttps://doi.org/10.1186/s12302-025-01146-1Aristolochic acid IApoptosis dysregulationComputational analysisIn silico multi-omics analysisTumor microenvironment |
| spellingShingle | Bitian Zhang Ping-Chung Leung Chun-Kwok Wong Dongjie Wang Aristolochic acid I orchestrates multi-organ carcinogenesis through apoptotic pathway in bladder, kidney, and liver cancers: a multi-omics dissection Environmental Sciences Europe Aristolochic acid I Apoptosis dysregulation Computational analysis In silico multi-omics analysis Tumor microenvironment |
| title | Aristolochic acid I orchestrates multi-organ carcinogenesis through apoptotic pathway in bladder, kidney, and liver cancers: a multi-omics dissection |
| title_full | Aristolochic acid I orchestrates multi-organ carcinogenesis through apoptotic pathway in bladder, kidney, and liver cancers: a multi-omics dissection |
| title_fullStr | Aristolochic acid I orchestrates multi-organ carcinogenesis through apoptotic pathway in bladder, kidney, and liver cancers: a multi-omics dissection |
| title_full_unstemmed | Aristolochic acid I orchestrates multi-organ carcinogenesis through apoptotic pathway in bladder, kidney, and liver cancers: a multi-omics dissection |
| title_short | Aristolochic acid I orchestrates multi-organ carcinogenesis through apoptotic pathway in bladder, kidney, and liver cancers: a multi-omics dissection |
| title_sort | aristolochic acid i orchestrates multi organ carcinogenesis through apoptotic pathway in bladder kidney and liver cancers a multi omics dissection |
| topic | Aristolochic acid I Apoptosis dysregulation Computational analysis In silico multi-omics analysis Tumor microenvironment |
| url | https://doi.org/10.1186/s12302-025-01146-1 |
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