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However, the ultrasmall particle size of Ag2Se QDs allows them to cross the blood\u2013brain barrier, thus potentially affecting the central nervous system. Therefore, risk assessment and response strategies for Ag2Se QDs are important. The adverse outcome pathway (AOP) framework makes it possible to develop risk management strategies based on toxicity mechanisms. In this study, using the AOP framework, we constructed causal mechanism relationship diagrams at different biological levels of Ag2Se QD neurotoxicity. In this framework, excess mitochondrial reactive oxygen species (mtROS) triggered Nod-like receptor protein 3 (NLRP3) inflammasome activation in microglia was molecular initiation event (MIE). Proinflammatory mediator secretion and microglia activation were key events (KEs) at the cellular level. Neuroinflammation and neuronal damage were KEs at the organ\/tissue level. Altered hippocampal physiology was the adverse outcome (AO) at the individual level. Based on the established AOP framework, further studies confirmed that mtROS-activated nuclear-factor-E2-related factor 2 (Nrf2)\/PTEN-induced kinase 1 (PINK1)- mitophagy contributed to weaken the MIE. Molecular docking-assisted molecular biology experiments demonstrated that quercetin (Qu) enhanced this process. This article emphasizes the importance of the AOP in the risk management of nanomaterials. Furthermore, this paper guides the use of natural small-molecule drugs as a strategy to mitigate nanomaterial-induced neurotoxicity.<\/jats:p>","DOI":"10.1021\/acsnano.4c16813","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T16:12:57Z","timestamp":1741623177000},"page":"11029-11048","source":"Crossref","is-referenced-by-count":23,"title":["Adverse Outcome\nPathway-Based Strategies to Mitigate\nAg2Se Quantum Dot-Induced Neurotoxicity"],"prefix":"10.1021","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9141-5890","authenticated-orcid":true,"given":"Yongshuai","family":"Yao","sequence":"first","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Wang","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 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People\u2019s Republic of China, 210009"]},{"name":"Westlake University School of Medicine , , ,","place":["Hangzhou, People\u2019s Republic of China, 310006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyue","family":"Zou","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]},{"name":"Nanjing University of Chinese Medicine , , ,","place":["Nanjing, People\u2019s Republic of China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiru","family":"Niu","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Hu","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Fang","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Wang","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]},{"name":"Taizhou Center for Disease Control and Prevention , ,","place":["Taizhou, People\u2019s Republic of China, 318000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Qiao","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]},{"name":"Gusu District Center for Disease Control and Prevention , ,","place":["Soochow, People\u2019s Republic of China, 215000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congcong","family":"Li","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]},{"name":"Yancheng Kindergarten Teachers College , ,","place":["Yancheng, People\u2019s Republic of China, 224005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujing","family":"Guan","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s Republic of China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuying","family":"Xue","sequence":"additional","affiliation":[{"name":"Southeast University , , ,","place":["Nanjing, People\u2019s 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Pollut."},{"key":"2026081813173857000_cit37","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102413","article-title":"Ncoa4-Mediated Ferritinophagy\nis Involved in Ionizing Radiation-Induced Ferroptosis of Intestinal\nEpithelial Cells","volume":"55","author":"Zhou","year":"2022","journal-title":"Redox Biol."},{"key":"2026081813173857000_cit38","doi-asserted-by":"publisher","DOI":"10.1016\/j.impact.2021.100367","article-title":"Protein Corona Mitigated the Cytotoxicity\nof CdTe QDs to Macrophages\nby Targeting Mitochondria","volume":"25","author":"Liu","year":"2022","journal-title":"Nanoimpact."},{"issue":"11","key":"2026081813173857000_cit39","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1038\/s41419-018-1152-2","article-title":"Pink1\/Parkin-Mediated\nMitophagy is\nActivated in Cisplatin Nephrotoxicity to Protect Against Kidney Injury","volume":"9","author":"Wang","year":"2018","journal-title":"Cell Death Dis."},{"key":"2026081813173857000_cit40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2022.129043","article-title":"The Role of Ferroptosis\nMediated by Nrf2\/Erk-Regulated Ferritinophagy in CdTe QDs-Induced\nInflammation in Macrophage","volume":"436","author":"Liu","year":"2022","journal-title":"J. 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