{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T16:03:40Z","timestamp":1779725020152,"version":"3.53.1"},"reference-count":65,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"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":"publisher","award":["82571825"],"award-info":[{"award-number":["82571825"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003787","name":"Natural Science Foundation of Hebei Province","doi-asserted-by":"publisher","award":["H2025206168"],"award-info":[{"award-number":["H2025206168"]}],"id":[{"id":"10.13039\/501100003787","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003787","name":"Natural Science Foundation of Hebei Province","doi-asserted-by":"publisher","award":["H2023206266"],"award-info":[{"award-number":["H2023206266"]}],"id":[{"id":"10.13039\/501100003787","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Industry-University-Research Project of Universities Stationed in Hebei Collaborative with Shijiazhuang","award":["241200073A"],"award-info":[{"award-number":["241200073A"]}]},{"name":"Hebei Province International Science and Technology Cooperation Key Project","award":["25292401D"],"award-info":[{"award-number":["25292401D"]}]},{"name":"Scientific Research Project of Higher Education Institutions in Hebei Province","award":["CXZX2025007"],"award-info":[{"award-number":["CXZX2025007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Rotenone is a widely used environmental pesticide, and epidemiological studies suggest that exposure is associated with an increased risk of Parkinson\u2019s disease (PD); however, the molecular toxicological basis of this association remains incompletely defined. Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that is relevant to PD and other neurodegenerative disorders. In this study, we provide disease-contextual functional evidence linking ferroptosis to rotenone-induced PD-like neurotoxicity. Methods: We combined network toxicology, human PD substantia nigra transcriptomic analysis using GSE7621, and SH-SY5Y cell-based validation. Rotenone-associated targets were predicted and analyzed for ferroptosis-related enrichment, PD transcriptomic signatures were used for disease-contextual candidate prioritization, and selected findings were validated using qPCR, CCK-8, Western blotting, C11-BODIPY lipid peroxidation staining, and transmission electron microscopy. Results: By further integrating a human PD substantia nigra transcriptomic dataset (GSE7621), we prioritized an 11-gene, PD-contextualized ferroptosis-associated candidate module (LIPF, FAM170A, MCHR1, IL17A, MYB, GFAP, ARMC3, GKN1, GATA3, IL17F, and TEKT1). In SH-SY5Y cells, rotenone exposure consistently upregulated this candidate transcriptional module, and this induction was broadly attenuated by the ferroptosis inhibitor ferrostatin-1 (Fer-1). In parallel, orthogonal functional assays supported an iron- and lipid peroxidation-driven injury state under rotenone exposure that was suppressible by ferroptosis inhibition and iron chelation. Finally, we further performed an exploratory drug\u2013gene association screen to prioritize clinically available candidates, and a limited qPCR check suggested that several selected compounds partially attenuated representative hub-gene induction under rotenone exposure. Conclusions: Collectively, these findings provide disease-contextual and experimentally supported evidence linking rotenone exposure to ferroptosis-associated neurotoxicity, and identify a ferroptosis-responsive transcriptional module for future hypothesis-driven mechanistic investigation.<\/jats:p>","DOI":"10.3390\/cells15110959","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T15:05:08Z","timestamp":1779721508000},"page":"959","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Network Toxicology and Transcriptomic Analyses Reveal Ferroptosis-Related Neurotoxicity of Rotenone as an Environmental Hazardous Compound"],"prefix":"10.3390","volume":"15","author":[{"given":"Yimeng","family":"Chen","sequence":"first","affiliation":[{"name":"Hebei Medical University-University of Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Ma","sequence":"additional","affiliation":[{"name":"Hebei Medical University-University of Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang 050017, China"},{"name":"Hebei Technology Innovation Center for Stem Cell and Regenerative Medicine, Shijiazhuang 050017, China"},{"name":"Hebei International Joint Research Center for Stem Cell and Regenerative Medicine, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixin","family":"Li","sequence":"additional","affiliation":[{"name":"Hebei Medical University-University of Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang 050017, China"},{"name":"Hebei Technology Innovation Center for Stem Cell and Regenerative Medicine, Shijiazhuang 050017, China"},{"name":"Hebei International Joint Research Center for Stem Cell and Regenerative Medicine, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingrong","family":"Xu","sequence":"additional","affiliation":[{"name":"Hebei Medical University-University of Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang 050017, China"},{"name":"Hebei Technology Innovation Center for Stem Cell and Regenerative Medicine, Shijiazhuang 050017, China"},{"name":"Hebei International Joint Research Center for Stem Cell and Regenerative Medicine, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuixia","family":"Ma","sequence":"additional","affiliation":[{"name":"Hebei Medical University-University of 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Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2843-0769","authenticated-orcid":false,"given":"Jun","family":"Ma","sequence":"additional","affiliation":[{"name":"Hebei Medical University-University of Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang 050017, China"},{"name":"Hebei Technology Innovation Center for Stem Cell and Regenerative Medicine, Shijiazhuang 050017, China"},{"name":"Hebei International Joint Research Center for Stem Cell and Regenerative Medicine, Shijiazhuang 050017, China"},{"name":"Human Anatomy Department, Hebei Medical University, Shijiazhuang 050017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7395-2094","authenticated-orcid":false,"given":"Huixian","family":"Cui","sequence":"additional","affiliation":[{"name":"Hebei 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