{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T04:22:28Z","timestamp":1787718148288,"version":"build-2784847793"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32402415"],"award-info":[{"award-number":["32402415"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["2025AFB721"],"award-info":[{"award-number":["2025AFB721"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Insects"],"abstract":"<jats:p>Metabolic resistance is commonly attributed to the overexpression of detoxification enzymes, whereas the metabolic systems that sustain detoxification remain less well resolved. Here, we integrated widely targeted metabolomics and transcriptomics to compare the clothianidin-resistant brown planthopper strain CLR with the susceptible strain CLS and validated candidate genes in an independent nitenpyram-resistant background. CLR and CLS exhibited distinct metabolomic profiles. Differential genes and metabolites converged on carbon metabolism, glycolysis\/gluconeogenesis, the tricarboxylic acid cycle, glutathione metabolism, pentose and glucuronate interconversions, cytochrome P450-mediated xenobiotic metabolism, and ABC transporters. These changes were summarized into four interconnected modules involving glycolytic energy supply, protective sugar-derived metabolites, pyruvate\u2013TCA\u2013malate metabolism, and UGT-mediated glycosylation. Expression analysis identified a mitochondrial NADP-dependent isocitrate dehydrogenase gene and UDP-glucosyltransferase 2 (UGT2) as consistently upregulated in both resistant backgrounds. Silencing NADP reduced the LC50 of nitenpyram and clothianidin by 1.84- and approximately 1.81-fold, respectively, whereas UGT2 silencing produced corresponding reductions of 1.89- and 1.83-fold. These findings indicate that neonicotinoid resistance in Nilaparvata lugens is supported by coordinated remodelling of central metabolism and detoxification and identify two candidate metabolic nodes for further resistance management research.<\/jats:p>","DOI":"10.3390\/insects17090884","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:49:34Z","timestamp":1787582974000},"page":"884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Reprogramming Supports Neonicotinoid Resistance in the Brown Planthopper, Nilaparvata lugens"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8328-4197","authenticated-orcid":false,"given":"Guijian","family":"Zhang","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory for Crop Diseases & Insect Pests & Weeds Control, Key Laboratory of Integrated Pests Management on Crops in Central China of Ministry of Agricultural and Rural Affairs, Institute of Plant Protection and Soil Science, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Hubei Insect Resources Utilization and Sustainable Pest Management Key Laboratory, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangqian","family":"Chang","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory for Crop Diseases & Insect Pests & Weeds Control, Key Laboratory of Integrated Pests Management on Crops in Central China of Ministry of Agricultural and Rural Affairs, Institute of Plant Protection and Soil Science, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Lv","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory for Crop Diseases & Insect Pests & Weeds Control, Key Laboratory of Integrated Pests Management on Crops in Central China of Ministry of Agricultural and Rural Affairs, Institute of Plant Protection and Soil Science, Hubei Academy of Agricultural Sciences, Wuhan 430064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1186\/s13059-014-0521-0","article-title":"Genomes of the Rice Pest Brown Planthopper and Its Endosymbionts Reveal Complex Complementary Contributions for Host Adaptation","volume":"15","author":"Xue","year":"2014","journal-title":"Genome Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1146\/annurev-ento-020117-043042","article-title":"Neonicotinoids and Other Insect Nicotinic Receptor Competitive Modulators: Progress and Prospects","volume":"63","author":"Casida","year":"2018","journal-title":"Annu. Rev. Entomol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.cois.2018.09.009","article-title":"Neonicotinoids: Molecular Mechanisms of Action, Insights into Resistance and Impact on Pollinators","volume":"30","author":"Ihara","year":"2018","journal-title":"Curr. Opin. Insect Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2897","DOI":"10.1021\/jf101303g","article-title":"Overview of the Status and Global Strategy for Neonicotinoids","volume":"59","author":"Jeschke","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107415","DOI":"10.1016\/j.phrs.2024.107415","article-title":"Insight of Neonicotinoid Insecticides: Exploring Exposure, Mechanisms in Non-Target Organisms, and Removal Technologies","volume":"209","author":"Zhang","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.pestbp.2015.04.004","article-title":"The Global Status of Insect Resistance to Neonicotinoid Insecticides","volume":"121","author":"Bass","year":"2015","journal-title":"Pestic. Biochem. Phys."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/brv.12440","article-title":"The Evolutionary Origins of Pesticide Resistance","volume":"94","author":"Hawkins","year":"2019","journal-title":"Biol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.pestbp.2014.11.014","article-title":"IRAC: Mode of Action Classification and Insecticide Resistance Management","volume":"121","author":"Sparks","year":"2015","journal-title":"Pestic. Biochem. Phys."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Li, J., Zhu, C., Xu, Y., He, H., Zhao, C., and Yan, F. (2024). Molecular Mechanism Underlying ROS-Mediated AKH Resistance to Imidacloprid in Whitefly. Insects, 15.","DOI":"10.3390\/insects15060436"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1146\/annurev-ento-070621-061328","article-title":"The Role of Cytochrome P450s in Insect Toxicology and Resistance","volume":"67","author":"Nauen","year":"2022","journal-title":"Annu. Rev. Entomol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1111\/j.1365-2583.2011.01105.x","article-title":"Overexpression of a Cytochrome P450 Monooxygenase, CYP6ER1, Is Associated with Resistance to Imidacloprid in the Brown Planthopper, Nilaparvata lugens","volume":"20","author":"Bass","year":"2011","journal-title":"Insect Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ibmb.2013.11.001","article-title":"The ABC Gene Family in Arthropods: Comparative Genomics and Role in Insecticide Transport and Resistance","volume":"45","author":"Dermauw","year":"2014","journal-title":"Insect Biochem. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev.pharmtox.45.120403.095857","article-title":"Glutathione Transferases","volume":"45","author":"Hayes","year":"2005","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1152\/physrev.00058.2017","article-title":"The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms","volume":"99","author":"Meech","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_15","first-page":"1","article-title":"ABC Transporters and Their Role in Protecting Insects from Pesticides and Their Metabolites","volume":"Volume 46","author":"Merzendorfer","year":"2014","journal-title":"Advances in Insect Physiology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 Enzymes in Drug Metabolism: Regulation of Gene Expression, Enzyme Activities, and Impact of Genetic Variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eaaw5473","DOI":"10.1126\/science.aaw5473","article-title":"Metabolic Reprogramming and Cancer Progression","volume":"368","author":"Faubert","year":"2020","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Yang, H.-C., Wu, Y.-H., Yen, W.-C., Liu, H.-Y., Hwang, T.-L., Stern, A., and Chiu, D.T.-Y. (2019). The Redox Role of G6PD in Cell Growth, Cell Death, and Cancer. Cells, 8.","DOI":"10.3390\/cells8091055"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1146\/annurev.biochem.76.061005.092322","article-title":"Glycosyltransferases: Structures, Functions, and Mechanisms","volume":"77","author":"Lairson","year":"2008","journal-title":"Annu. Rev. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1126\/science.1074170","article-title":"A Single P450 Allele Associated with Insecticide Resistance in Drosophila","volume":"297","author":"Daborn","year":"2002","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/ps.4470","article-title":"Resistance Evolution in Drosophila: The Case of CYP6G1","volume":"73","author":"Hilliou","year":"2017","journal-title":"Pest Manag. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Djouaka, R.F., Bakare, A.A., Coulibaly, O.N., Akogbeto, M.C., Ranson, H., Hemingway, J., and Strode, C. (2008). Expression of the Cytochrome P450s, CYP6P3 and CYP6M2 Are Significantly Elevated in Multiple Pyrethroid Resistant Populations of Anopheles Gambiae s.s. from Southern Benin and Nigeria. BMC Genom., 9.","DOI":"10.1186\/1471-2164-9-538"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.ibmb.2011.02.003","article-title":"Cytochrome P450 6M2 from the Malaria Vector Anopheles Gambiae Metabolizes Pyrethroids: Sequential Metabolism of Deltamethrin Revealed","volume":"41","author":"Stevenson","year":"2011","journal-title":"Insect Biochem. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.ibmb.2008.03.008","article-title":"Over-Expression of Cytochrome P450 CYP6CM1 Is Associated with High Resistance to Imidacloprid in the B and Q Biotypes of Bemisia Tabaci (Hemiptera: Aleyrodidae)","volume":"38","author":"Karunker","year":"2008","journal-title":"Insect Biochem. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nrm3314","article-title":"Metabolomics: The Apogee of the Omics Trilogy","volume":"13","author":"Patti","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"107739","DOI":"10.1016\/j.biotechadv.2021.107739","article-title":"Using Machine Learning Approaches for Multi-Omics Data Analysis: A Review","volume":"49","author":"Reel","year":"2021","journal-title":"Biotechnol. Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"117793221989905","DOI":"10.1177\/1177932219899051","article-title":"Multi-Omics Data Integration, Interpretation, and Its Application","volume":"14","author":"Subramanian","year":"2020","journal-title":"Bioinform. Biol. Insights"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.pestbp.2018.12.008","article-title":"Overexpression of CYP6ER1 associated with clothianidin resistance in Nilaparvata lugens (St\u00e5l)","volume":"154","author":"Jin","year":"2019","journal-title":"Pestic. Biochem. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.pestbp.2019.03.001","article-title":"Characterization of nitenpyram resistance in Nilaparvata lugens (St\u00e5l)","volume":"157","author":"Mao","year":"2019","journal-title":"Pestic. Biochem. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41522-023-00369-5","article-title":"Microbiome variation correlates with the insecticide susceptibility in different geographic strains of a significant agricultural pest, Nilaparvata lugens","volume":"9","author":"Zhang","year":"2023","journal-title":"npj Biofilms Microbiomes"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhang, B., Zhang, M., Jia, X., Hu, G., Ren, F., Fan, X., and Dong, Y. (2023). Integrated transcriptome and metabolome dissecting interaction between Vitis vinifera L. and Grapevine fabavirus. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043247"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jing, S., Wang, F., Ren, A., Zheng, F., Yu, B., Xu, J., Liu, Y., Yang, J., Chen, R., and Zeng, W. (2024). Identification and functional analysis of three NlCstF genes in Nilaparvata lugens. Insects, 15.","DOI":"10.3390\/insects15110867"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"34992","DOI":"10.1038\/srep34992","article-title":"Functional Analysis of CYP6ER1, a P450 Gene Associated with Imidacloprid Resistance in Nilaparvata Lugens","volume":"6","author":"Pang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.pestbp.2018.06.014","article-title":"Mechanisms of Resistance to Thiamethoxam and Dinotefuran Compared to Imidacloprid in the Brown Planthopper: Roles of Cytochrome P450 Monooxygenase and a P450 Gene CYP6ER1","volume":"150","author":"Sun","year":"2018","journal-title":"Pestic. Biochem. Phys."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4163","DOI":"10.1021\/acs.jafc.2c07692","article-title":"Importance of CYP6ER1 Was Different among Neonicotinoids in Their Susceptibility in Nilaparvata Lugens","volume":"71","author":"Zhang","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4476","DOI":"10.1002\/ps.6482","article-title":"Activator Protein-1 Mediated CYP6ER1 Overexpression in the Clothianidin Resistance of Nilaparvata Lugens (St\u00e5l)","volume":"77","author":"Jin","year":"2021","journal-title":"Pest Manag. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"127490","DOI":"10.1016\/j.chemosphere.2020.127490","article-title":"Adipokinetic Hormone Regulates Cytochrome P450-Mediated Imidacloprid Resistance in the Brown Planthopper, Nilaparvata Lugens","volume":"259","author":"Tang","year":"2020","journal-title":"Chemosphere"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7695","DOI":"10.1021\/acs.jafc.5c00803","article-title":"JNK-ERK Synergistic Regulation of P450 Gene Expression Confers Nitenpyram Resistance in Nilaparvata Lugens (St\u00e5l)","volume":"73","author":"Zhang","year":"2025","journal-title":"J. Agric. Food Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1111\/imb.12313","article-title":"Cycle Affects Imidacloprid Efficiency by Mediating Cytochrome P450 Expression in the Brown Planthopper Nilaparvata Lugens","volume":"26","author":"Kang","year":"2017","journal-title":"Insect Mol. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s10340-020-01294-8","article-title":"Antibiotics Increased Host Insecticide Susceptibility via Collapsed Bacterial Symbionts Reducing Detoxification Metabolism in the Brown Planthopper, Nilaparvata lugens","volume":"94","author":"Tang","year":"2021","journal-title":"J. Pest Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3693","DOI":"10.1038\/s41396-021-01046-1","article-title":"Decline in Symbiont-Dependent Host Detoxification Metabolism Contributes to Increased Insecticide Susceptibility of Insects under High Temperature","volume":"15","author":"Zhang","year":"2021","journal-title":"ISME J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"16168","DOI":"10.1074\/jbc.M010120200","article-title":"Control of Mitochondrial Redox Balance and Cellular Defense against Oxidative Damage by Mitochondrial NADP+-Dependent Isocitrate Dehydrogenase","volume":"276","author":"Jo","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4159","DOI":"10.1002\/ps.6453","article-title":"Dual Oxidase-dependent Reactive Oxygen Species Are Involved in the Regulation of UGT Overexpression-mediated Clothianidin Resistance in the Brown Planthopper, Nilaparvata lugens","volume":"77","author":"Zhang","year":"2021","journal-title":"Pest Manag. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"137074","DOI":"10.1016\/j.cej.2022.137074","article-title":"CeO2 Nanohybrid as a Synergist for Insecticide Resistance Management","volume":"446","author":"Zeng","year":"2022","journal-title":"Chem. Eng. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5771","DOI":"10.1002\/ps.8307","article-title":"A Putative Endonuclease Reduces the Efficiency of Oral RNA Interference in Nilaparvata Lugens","volume":"80","author":"Gao","year":"2024","journal-title":"Pest Manag. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6201","DOI":"10.1002\/ps.8966","article-title":"A Novel Strategy to Combat Insecticide Resistance in Insect Pest with a Nanoparticle-based Fusion DSRNA Delivery System","volume":"81","author":"He","year":"2025","journal-title":"Pest Manag. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"165188","DOI":"10.1016\/j.cej.2025.165188","article-title":"Nanoparticles Co-Delivering Double-Stranded RNA and Insecticide Enhance Control Efficacy and Overcome Pest Resistance","volume":"519","author":"Hu","year":"2025","journal-title":"Chem. Eng. J."}],"container-title":["Insects"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4450\/17\/9\/884\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T04:16:09Z","timestamp":1787717769000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4450\/17\/9\/884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":49,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["insects17090884"],"URL":"https:\/\/doi.org\/10.3390\/insects17090884","relation":{},"ISSN":["2075-4450"],"issn-type":[{"value":"2075-4450","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,24]]}}}