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Marine-derived polysaccharides, particularly those from Enteromorpha prolifera (PEPs), exhibit neuroprotective and anti-inflammatory properties\u2014yet their therapeutic potential for ASD remains unexplored. Major monosaccharide components of PEPs were identified as rhamnose, xylose, glucose, glucuronic acid, galactose, and ribose through ion chromatography analysis. Infrared spectroscopy confirmed PEPs as pyranose-type polysaccharides with \u03b1-glycosidic bonds and uronic acids, while gel permeation chromatography showed a predominant molecular weight of 3.813 kDa (83.919%). To explore the therapeutic potential of PEPs in ASD, a comprehensive method combining network pharmacology, molecular docking, and in vitro validation was conducted. A total of 235 ASD-related target proteins were predicted, with enrichment analyses indicating significant involvement in pathways such as neuroactive ligand\u2013receptor interaction and the MAPK signaling pathway. In vitro assays using valproic acid (VPA)-induced HT22 neuronal cells showed that PEPs significantly attenuated apoptosis. Western blot analysis further confirmed the downregulation of HSP90AA1, cleaved CASP3\/pro-CASP3, p-NF-\u03baB1\/NF-\u03baB1, p-AKT1\/AKT, and p-mTOR\/mTOR, as well as the upregulation of I\u03baB\u03b1 after PEPs treatment. These findings suggest that PEPs exert neuroprotective effects through the modulation of apoptosis and inflammation-related signaling pathways, supporting their potential as a promising candidate for further study in ASD.<\/jats:p>","DOI":"10.3390\/cimb47100796","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T13:48:05Z","timestamp":1758808085000},"page":"796","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enteromorpha prolifera Polysaccharides Alleviate Valproic Acid-Induced Neuronal Apoptosis in a Cellular Model of Autism Spectrum Disorder"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3463-1050","authenticated-orcid":false,"given":"Xulan","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen 361023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Su","sequence":"additional","affiliation":[{"name":"School of Public Health, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen 361023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Public Health, Fujian Medical University, Fuzhou 350122, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen 361023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8806-2621","authenticated-orcid":false,"given":"Xiaochun","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen 361023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3984-5970","authenticated-orcid":false,"given":"Juan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen 361023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"key":"ref_1","unstructured":"Association, A.P. 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