{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:08:54Z","timestamp":1788930534103,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFD1000800"],"award-info":[{"award-number":["2023YFD1000800"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["scijournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pest Management Science"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>\n                      Fluxametamide is a chiral isoxazoline insecticide widely used for pest control. However, the enantioselective biological activity and underlying mechanisms of its enantiomers remain poorly understood. This study aimed to systematically evaluate the enantioselective acaricidal activity of fluxametamide against\n                      <jats:italic>Tetranychus cinnabarinus<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Bioassays revealed pronounced enantioselectivity, with S\u2010(+)\u2010fluxametamide exhibiting significantly higher acaricidal activity than the racemate. Detoxification enzyme assays indicated significant induction of cytochrome P450 activity following sublethal exposure. Transcriptomic and RT\u2010qPCR analyses further identified multiple P450 genes responsive to fluxametamide, among which CYP392E7 and CYP392A16 were strongly up\u2010regulated. Molecular docking and molecular dynamics simulations demonstrated that R\u2010(\u2212)\u2010fluxametamide exhibited stronger and more stable binding to these P450 enzymes than the S\u2010(+) enantiomer. Functional assays using recombinant proteins confirmed that CYP392E7 preferentially metabolized R\u2010(\u2212)\u2010fluxametamide, whereas S\u2010(+)\u2010fluxametamide showed lower metabolic susceptibility. Electrophysiological analyses using two\u2010electrode voltage clamp recordings revealed that fluxametamide acts as a noncompetitive antagonist of RDL2\u2010mediated GABA currents without direct activation, with S\u2010(+)\u2010fluxametamide producing the strongest inhibitory effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>The enantioselective acaricidal activity of fluxametamide is governed by a dual mechanism involving preferential metabolic clearance of the R\u2010(\u2212)\u2010enantiomer and stronger target\u2010site inhibition by the S\u2010(+) enantiomer. These findings provide mechanistic insights into the stereoselective action of fluxametamide and highlight the importance of considering enantioselectivity in the development and risk assessment of chiral acaricides. \u00a9 2026 Society of Chemical Industry.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ps.71273","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:29:21Z","timestamp":1788928161000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic insights into the enantioselective activity of Fluxametamide in\n                    <i>Tetranychus cinnabarinus<\/i>"],"prefix":"10.1002","author":[{"given":"Xinyu","family":"Li","sequence":"first","affiliation":[{"name":"College of Plant Protection Southwest University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Cheng","sequence":"additional","affiliation":[{"name":"College of Plant Protection Southwest University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongyang","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Plant Protection Southwest University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Plant Protection Southwest University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyang","family":"Feng","sequence":"additional","affiliation":[{"name":"College of Plant Protection Southwest University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9661-8267","authenticated-orcid":false,"given":"Zhang","family":"Ping","sequence":"additional","affiliation":[{"name":"College of Plant Protection Southwest University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5491-5375","authenticated-orcid":false,"given":"Lin","family":"He","sequence":"additional","affiliation":[{"name":"College of Plant Protection Southwest University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8968-0855","authenticated-orcid":false,"given":"Zhifeng","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Plant Protection Southwest University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1073\/pnas.0408847102","article-title":"Enantioselectivity in environmental safety of current chiral insecticides","volume":"102","author":"Liu W","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.scitotenv.2022.159656","article-title":"Enantioselectivity in the toxicological effects of chiral pesticides: a review","volume":"857","author":"Ji C","year":"2022","journal-title":"Sci Total Environ"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1021\/es00008a022","article-title":"Environmental behavior of acetamide pesticide stereoisomers. 1. Stereoselective and enantioselective determination using chiral high\u2010resolution gas chromatography and chiral high\u2010performance liquid chromatography","volume":"29","author":"Buser HR","year":"1995","journal-title":"Environ Sci Technol"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"8405","DOI":"10.1021\/es300049q","article-title":"Enantioselective damage of diclofop acid mediated by oxidative stress and acetyl\u2010CoA carboxylase in nontarget plant Arabidopsis thaliana","volume":"46","author":"Zhang Q","year":"2012","journal-title":"Environ Sci Technol"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.2174\/1389203717666160413124239","article-title":"Enantioselective effects of chiral pesticides on their primary targets and secondary targets","volume":"18","author":"Ye Y","year":"2016","journal-title":"Curr Protein Pept Sci"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"13657","DOI":"10.1021\/acs.est.9b03697","article-title":"Development of S\u2010fluxametamide for bioactivity improvement and risk reduction: systemic evaluation of the novel insecticide fluxametamide at the enantiomeric level","volume":"53","author":"Li R","year":"2019","journal-title":"Environ Sci Technol"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.foodchem.2025.143017","article-title":"Enantioselection behaviors and risk assessments of chiral pesticide ethiprole and its chiral metabolite ethiprole amide in five kinds of vegetables","volume":"473","author":"Qu W","year":"2025","journal-title":"Food Chem"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.pestbp.2018.02.002","article-title":"Fluxametamide: a novel isoxazoline insecticide that acts via distinctive antagonism of insect ligand\u2010gated chloride channels","volume":"151","author":"Asahi M","year":"2018","journal-title":"Pestic Biochem Physiol"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1002\/ps.6084","article-title":"Status and outlook for acaricide and insecticide discovery","volume":"77","author":"Jeschke P","year":"2020","journal-title":"Pest Manag Sci"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.pestbp.2020.104587","article-title":"Insecticides, biologics and nematicides: updates to IRAC's mode of action classification a tool for resistance management","volume":"167","author":"Sparks TC","year":"2020","journal-title":"Pestic Biochem Physiol"},{"key":"e_1_2_10_12_1","article-title":"Resistance risk assessment in diamondback moth, Plutella xylostella (L.) to fluxametamide","volume":"163","author":"Roy D","year":"2023","journal-title":"Crop Prot"},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/chir.22796","article-title":"The influence of microbial communities for triadimefon enantiomerization in soils with different pH values","volume":"30","author":"Talab KMA","year":"2018","journal-title":"Chirality"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1016\/j.envpol.2018.09.095","article-title":"Enantioselectivity in biotransformation and bioaccumulation processes of typical chiral contaminants","volume":"243","author":"Xu C","year":"2018","journal-title":"Environ Pollut"},{"key":"e_1_2_10_15_1","first-page":"236","volume-title":"Insect Molecular Biology and Biochemistry","author":"Feyereisen R","year":"1999"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ibmb.2023.104039","article-title":"Contrasting roles of cytochrome P450s in amitraz and chlorfenapyr resistance in the crop pest Tetranychus urticae","volume":"164","author":"Vandenhole M","year":"2023","journal-title":"Insect Biochem Mol Biol"},{"key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"188","DOI":"10.2174\/138920009787522188","article-title":"Stereoselectivity in drug metabolism: molecular mechanisms and analytical methods","volume":"10","author":"Campo VL","year":"2009","journal-title":"Curr Drug Metab"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1080\/15287394.2022.2066038","article-title":"Biological activities and gene expression of detoxifying enzymes in Tribolium castaneum induced by Moutan cortex essential oil","volume":"85","author":"Li X","year":"2022","journal-title":"J Toxicol Environ Health A"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/S0166-2236(97)01127-2","article-title":"molecular biology of insect neuronal GABA receptors","volume":"20","author":"Hosie AM","year":"1997","journal-title":"Trends Neurosci"},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1021\/tx400055p","article-title":"New GABA\/glutamate receptor target for [3H] isoxazoline insecticide","volume":"26","author":"Garc\u00eda\u2010Reynaga P","year":"2013","journal-title":"Chem Res Toxicol"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.2174\/0929867324666170613075736","article-title":"Mechanisms of action, resistance and toxicity of insecticides targeting GABA receptors","volume":"24","author":"Buckingham SD","year":"2017","journal-title":"Curr Med Chem"},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-ento-120811-153645","article-title":"Neuroactive insecticides: targets, selectivity, resistance, and secondary effects","volume":"58","author":"Casida JE","year":"2013","journal-title":"Annu Rev Entomol"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/0305-0491(84)90396-1","article-title":"Monooxygenase activity of tobacco budworm (Heliothis virescens F.) larvae: tissue distribution and optimal assay conditions for the gut activity","volume":"79","author":"Shang CC","year":"1984","journal-title":"Comp Biochem Physiol B"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1006\/pest.1995.1018","article-title":"Cytochrome P450\u2010associated insecticide resistance and the development of biochemical diagnostic assays in Heliothis virescens","volume":"51","author":"Rose RL","year":"1995","journal-title":"Pestic Biochem Physiol"},{"key":"e_1_2_10_25_1","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/0022-1910(62)90074-4","article-title":"A study of housefly esterases by means of a sensitive colorimetric method","volume":"8","author":"Asperen K","year":"1962","journal-title":"J Insect Physiol"},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1042\/bst0190755","article-title":"Role of esterases in resistance of insects to insecticides","volume":"19","author":"Devonshire AL","year":"1991","journal-title":"Biochem Soc Trans"},{"key":"e_1_2_10_27_1","first-page":"7130","article-title":"Glutathione S\u2010transferases: the first enzymatic step in mercapturic acid formation","volume":"249","author":"Habig WH","year":"1974","journal-title":"J Biol Chem"},{"key":"e_1_2_10_28_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1042\/bj2170051","article-title":"Kinetic studies on a glutathione S\u2010transferase from the larvae of Costelytra zealandica","volume":"217","author":"Clark AG","year":"1984","journal-title":"Biochem J"},{"key":"e_1_2_10_29_1","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein\u2010dye binding","volume":"72","author":"Bradford MM","year":"1976","journal-title":"Anal Biochem"},{"key":"e_1_2_10_30_1","unstructured":"Premier Biosoft International Primer Premier 5 (Version 5.0) [Computer software]. Premier Biosoft International Palo Alto CA(2005)."},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real\u2010time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak KJ","year":"2001","journal-title":"Methods"},{"key":"e_1_2_10_32_1","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS\u2010MODEL: homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse A","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"e_1_2_10_33_1","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott O","year":"2010","journal-title":"J Comput Chem"},{"key":"e_1_2_10_34_1","first-page":"84","volume-title":"Scalable algorithms for molecular dynamics simulations on commodity clusters. SC '06: Proceedings of the 2006 ACM\/IEEE Conference on Supercomputing; 2006 Nov 11\u201317","author":"Bowers KJ","year":"2006"},{"key":"e_1_2_10_35_1","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.pestbp.2020.01.010","article-title":"The interaction between abamectin and RDL in the carmine spider mite: a target site and resistant mechanism study","volume":"164","author":"Xu Z","year":"2020","journal-title":"Pestic Biochem Physiol"},{"key":"e_1_2_10_36_1","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1021\/acs.jafc.4c07841","article-title":"Enantioselectivity mechanism of Etoxazole enantiomers in Tetranychus cinnabarinus: acaricidal activity, metabolic difference, and target binding","volume":"73","author":"Guo XX","year":"2025","journal-title":"J Agric Food Chem"},{"key":"e_1_2_10_37_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ibmb.2021.103709","article-title":"Over\u2010expression in cis of the midgut P450 CYP392A16 contributes to abamectin resistance in Tetranychus urticae","volume":"142","author":"Papapostolou KM","year":"2022","journal-title":"Insect Biochem Mol Biol"},{"key":"e_1_2_10_38_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ibmb.2015.09.004","article-title":"Functional characterization of the Tetranychus urticae CYP392A11, a cytochrome P450 that hydroxylates the METI acaricides cyenopyrafen and fenpyroximate","volume":"65","author":"Riga M","year":"2015","journal-title":"Insect Biochem Mol Biol"},{"key":"e_1_2_10_39_1","article-title":"Pyrethroid stereoisomerism: diastereomeric and enantiomeric selectivity in environmental matrices a review","volume":"10","author":"Parente CET","year":"2018","journal-title":"Orbital Electron J Chem"},{"key":"e_1_2_10_40_1","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.ibmb.2013.03.007","article-title":"Molecular analysis of resistance to acaricidal spirocyclic tetronic acids in Tetranychus urticae: CYP392E10 metabolizes spirodiclofen, but not its corresponding enol","volume":"43","author":"Demaeght P","year":"2013","journal-title":"Insect Biochem Mol Biol"},{"key":"e_1_2_10_41_1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/ps.7187","article-title":"activity, selection response and molecular mode of action of the isoxazoline afoxolaner in Tetranychus urticae","volume":"79","author":"Mermans C","year":"2023","journal-title":"Pest Manag Sci"},{"key":"e_1_2_10_42_1","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1021\/acs.jafc.2c07924","article-title":"Enantioselective degradation and bioactivity mechanism of a new chiral fungicide Fluindapyr in Paddy ecosystems","volume":"71","author":"Tong Z","year":"2023","journal-title":"J Agric Food Chem"}],"container-title":["Pest Management Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/scijournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ps.71273","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/scijournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ps.71273","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/scijournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ps.71273","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:29:29Z","timestamp":1788928169000},"score":1,"resource":{"primary":{"URL":"https:\/\/scijournals.onlinelibrary.wiley.com\/doi\/10.1002\/ps.71273"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,8]]},"references-count":41,"alternative-id":["10.1002\/ps.71273"],"URL":"https:\/\/doi.org\/10.1002\/ps.71273","archive":["Portico"],"relation":{},"ISSN":["1526-498X","1526-4998"],"issn-type":[{"value":"1526-498X","type":"print"},{"value":"1526-4998","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,8]]},"assertion":[{"value":"2026-04-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ps.71273"}}