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This study investigated whether Saposhnikoviae Radix (SR) aqueous extract protects against arsenic-induced neurotoxicity by modulating pyroptosis. Kunming mice were exposed to NaAsO2 (10 mg\/kg) with or without SR (3, 6, 12 g\/kg). NaAsO2 exposure induced anxiety-like behaviors and spatial memory deficits, accompanied by widespread neuronal damage (hippocampal pyramidal cell disarray, cerebellar Purkinje cell loss, and cortical vacuolation) and upregulation of pyroptosis-related proteins (NLRP3, Cleaved-Caspase-1, GSDMD-N, IL-1\u03b2, IL-18) in brain tissues. SR treatment significantly ameliorated these behavioral and pathological changes. In HT22 cells, NaAsO2 (12.5 \u03bcM) reduced cell viability, increased LDH release, induced pyroptotic ultrastructural features (membrane blebbing and pore formation), and upregulated pyroptosis markers; SR (400 \u03bcg\/mL) effectively reversed these effects. Mechanistically, SR suppressed the NLRP3\/Caspase-1\/GSDMD axis activation, as confirmed by both protein and mRNA analyses. These findings demonstrate that SR aqueous extract attenuates arsenic-induced central nervous system injury through specific inhibition of the pyroptosis pathway, providing an experimental basis for the potential use of traditional Chinese medicine in preventing environmental metalloid-induced neurotoxicity.<\/jats:p>","DOI":"10.3390\/toxics14080706","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:10:24Z","timestamp":1786374624000},"page":"706","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aqueous Extract of Saposhnikoviae Radix Antagonizes Arsenic Neurotoxicity via the NLRP3\/Caspase-1\/GSDMD Pyroptotic Axis: Translating Environmental Exposure into Neuropathology and Herbal Recalibration"],"prefix":"10.3390","volume":"14","author":[{"given":"Xiao-Ping","family":"Zeng","sequence":"first","affiliation":[{"name":"Key Laboratory for Basic and Clinical Research of Cardiovascular Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Guizhou Medical University, Guian New Area, Guiyang 561113, China"},{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, School of Pharmacy, Guizhou Medical University, Guian New Area, Guiyang 561113, China"},{"name":"Natural Products Research Center of Guizhou Province, Guiyang 550014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory for Basic and Clinical Research of Cardiovascular Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Guizhou Medical University, Guian New Area, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, School of Pharmacy, Guizhou Medical University, Guian New Area, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7947-8426","authenticated-orcid":false,"given":"Ji-Gang","family":"Pan","sequence":"additional","affiliation":[{"name":"Key Laboratory for Basic and Clinical Research of Cardiovascular Diseases, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Guizhou Medical University, Guian New Area, Guiyang 561113, China"},{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, School of Pharmacy, Guizhou Medical University, Guian New Area, Guiyang 561113, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1126\/science.aba1510","article-title":"Global threat of arsenic in groundwater","volume":"368","author":"Podgorski","year":"2020","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"117940","DOI":"10.1016\/j.envpol.2021.117940","article-title":"Environmental arsenic exposure and its contribution to human diseases, toxicity mechanism and management","volume":"289","author":"Rahaman","year":"2021","journal-title":"Environ. 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