{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Aldo‐keto reductase family 7 member A3 (AKR7A3) is emerging as a multifunctional enzyme that plays a critical role in the detoxification of reactive aldehydes and xenobiotic metabolites and in the cellular defense against oxidative stress. In several experimental models, AKR7A3 is induced as part of an adaptive response mediated by the NRF2 pathway when cells are challenged by toxic agents such as aflatoxins, psoralen/isopsoralen, oxfendazole, etofenprox, and β‐naphthoflavone (see, for example."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": " Such induction facilitates the reduction of toxic dialdehyde intermediates—such as those generated from aflatoxin B₁ and lipid peroxidation—and helps to minimize the formation of DNA and protein adducts. In parallel, pharmacogenomic studies have shown that genetic variations in AKR7A3 may alter drug metabolism and contribute to adverse reactions, for instance, influencing bleeding risks in patients treated with rivaroxaban."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In hepatic models, transient up‐regulation of AKR7A3 appears to represent an early defensive response in non‐genotoxic hepatocarcinogenesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", as well as in settings of chemically induced liver injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Conversely, in clinical hepatocellular carcinoma samples, loss or down‐regulation of AKR7A3 has been correlated with aggressive tumor features, poor differentiation, and diminished overall survival—findings that support a tumor suppressor role for this enzyme through inhibition of key mitogenic and inflammatory signaling pathways (e.g., ERK, c‐Jun, and NF‐κB)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Moreover, in breast carcinoma patients, higher intratumoral levels of AKR7A3 have been associated with longer disease‐free survival"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", reinforcing its favorable prognostic significance. \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in the liver and breast, AKR7A3 is detectable in other tissues—including the heart and testis—and its expression levels modulate in response to various environmental and pharmacological challenges."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": " Its status as a drug‐metabolizing enzyme makes it a promising biomarker for oxidative stress and glutathione depletion"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and its modulation by chemopreventive agents such as quercetin further suggests potential therapeutic applications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, AKR7A3 functions as an important detoxifying enzyme by reducing reactive aldehyde metabolites, thereby protecting cells from oxidative damage. Its dynamic regulation—upregulated in acute adaptive responses yet diminished in certain advanced tumors—underscores a complex role in chemical carcinogenesis and tumor suppression. These multifaceted functions render AKR7A3 a potential diagnostic and prognostic biomarker, as well as a target for therapeutic intervention in oxidative stress–related liver injury and cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Julia Esperanza Torres-Mena, Karla Noemí Salazar-Villegas, Ricardo Sánchez-Rodríguez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aldo-Keto Reductases as Early Biomarkers of Hepatocellular Carcinoma: A Comparison Between Animal Models and Human HCC."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dig Dis Sci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10620-018-4943-5"}], "href": "https://doi.org/10.1007/s10620-018-4943-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29383608"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29383608"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Lei Song, Bin Yu, Li Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The mechanism of Psoralen and Isopsoralen hepatotoxicity as revealed by hepatic gene expression profiling in SD rats."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Basic Clin Pharmacol Toxicol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/bcpt.13287"}], "href": "https://doi.org/10.1111/bcpt.13287"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31271704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31271704"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Qian Yu, Yann-Yin Lee, Zheng-Yun Xia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S-allylmercaptocysteine improves nonalcoholic steatohepatitis by enhancing AHR/NRF2-mediated drug metabolising enzymes and reducing NF-κB/IκBα and NLRP3/6-mediated inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Nutr (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00394-020-02305-1"}], "href": "https://doi.org/10.1007/s00394-020-02305-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32556446"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32556446"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yuri Hojo, Ayako Shiraki, Takuma Tsuchiya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Liver tumor promoting effect of etofenprox in rats and its possible mechanism of action."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Toxicol Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2131/jts.37.297"}], "href": "https://doi.org/10.2131/jts.37.297"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22467020"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22467020"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Hitomi Hayashi, Eriko Taniai, Reiko Morita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Threshold dose of liver tumor promoting effect of β-naphthoflavone in rats."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Toxicol Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2131/jts.37.517"}], "href": "https://doi.org/10.2131/jts.37.517"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22687991"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22687991"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ming Zhao, Qiang Zhang, Xizi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Non-synonymous alterations in AKR7A3 and ABCA6 correlate with bleeding in aged patients treated with rivaroxaban."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Transl Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cts.13205"}], "href": "https://doi.org/10.1111/cts.13205"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34859601"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34859601"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Shan-Han Huang, Ying-Chi Lin, Chun-Wei Tung "}, {"type": "b", "children": [{"type": "t", "text": "Identification of Time-Invariant Biomarkers for Non-Genotoxic Hepatocarcinogen Assessment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Environ Res Public Health (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijerph17124298"}], "href": "https://doi.org/10.3390/ijerph17124298"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32560183"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32560183"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "María Paulette Castro-Gil, Julia Esperanza Torres-Mena, Rosa M Salgado, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The transcriptome of early GGT/KRT19-positive hepatocellular carcinoma reveals a downregulated gene expression profile associated with fatty acid metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ygeno.2021.11.035"}], "href": "https://doi.org/10.1016/j.ygeno.2021.11.035"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34861383"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34861383"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Raymond Kwok Kei Chow, Sarah Tsz-Kwan Sin, Ming Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AKR7A3 suppresses tumorigenicity and chemoresistance in hepatocellular carcinoma through attenuation of ERK, c-Jun and NF-κB signaling pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.12726"}], "href": "https://doi.org/10.18632/oncotarget.12726"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29137357"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29137357"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Viktor Hlaváč, Veronika Brynychová, Radka Václavíková, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of cytochromes p450 and aldo-keto reductases in prognosis of breast carcinoma patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Medicine (Baltimore) (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MD.0000000000000255"}], "href": "https://doi.org/10.1097/MD.0000000000000255"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25526449"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25526449"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jingzeng Cai, Jie Yang, Xiaoming Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Melatonin ameliorates trimethyltin chloride-induced cardiotoxicity: The role of nuclear xenobiotic metabolism and Keap1-Nrf2/ARE axis-mediated pyroptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biofactors (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/biof.1787"}], "href": "https://doi.org/10.1002/biof.1787"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34570919"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34570919"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Fei Li, Ya-guang Zou, Wen-bin Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The aged testis. A good model to find proteins involved in age-related changes of testis by proteomic analysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Reprod Med (2014)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24597284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24597284"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Adeola O Adebayo Michael, Nagib Ahsan, Valerie Zabala, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proteomic analysis of laser capture microdissected focal lesions in a rat model of progenitor marker-positive hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.15219"}], "href": "https://doi.org/10.18632/oncotarget.15219"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28199961"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28199961"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Weihua Gao, Yumiko Mizukawa, Noriyuki Nakatsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanism-based biomarker gene sets for glutathione depletion-related hepatotoxicity in rats."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Toxicol Appl Pharmacol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.taap.2010.06.015"}], "href": "https://doi.org/10.1016/j.taap.2010.06.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20621112"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20621112"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Tseye-Oidov Odbayar, Toshinori Kimura, Tojiro Tsushida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Isoenzyme-specific up-regulation of glutathione transferase and aldo-keto reductase mRNA expression by dietary quercetin in rat liver."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biochem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11010-009-0026-4"}], "href": "https://doi.org/10.1007/s11010-009-0026-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19191009"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19191009"}]}]}]}