{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T18:20:20Z","timestamp":1787595620806,"version":"build-2736575974"},"reference-count":58,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005851","name":"Shahid Beheshti University of Medical Sciences","doi-asserted-by":"publisher","award":["#43013354-3-1"],"award-info":[{"award-number":["#43013354-3-1"]}],"id":[{"id":"10.13039\/501100005851","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders whose underlying molecular mechanisms and biological processes remain incompletely understood. In this study, we used a multi-layered systems biology approach to prioritize candidate genes and regulatory factors associated with ASD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      Gene expression data from peripheral blood samples were obtained from the Gene Expression Omnibus (GEO) database (GSE18123). Using analyses performed in R software, differentially expressed genes (DEGs) in patients with ASD were identified (p-value\u2009&lt;\u20090.05 and |log\n                      <jats:sub>2<\/jats:sub>\n                      FC|\u2009&gt;\u20090.5). These DEGs were used to perform weighted gene co-expression network analysis (WGCNA) and construct a protein\u2013protein interaction (PPI) network. By integrating the results of these network analyses with feature selection techniques (LASSO and random forest feature importance), candidate genes associated with ASD were prioritized and evaluated using qRT-PCR in the valproic acid (VPA)-induced rat model of autism. Furthermore, a gene regulatory network (GRN) was constructed to identify the regulatory factors associated with DEGs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>\n                      <jats:italic>TLR8<\/jats:italic>\n                      and\n                      <jats:italic>CASP4<\/jats:italic>\n                      were prioritized as candidate genes that may be associated with ASD, because they were located within the co-expression module that showed the strongest correlation with ASD, were identified as key nodes of the PPI network, and were selected by feature selection algorithms. Our experimental validation showed increased expression of\n                      <jats:italic>TLR8<\/jats:italic>\n                      and\n                      <jats:italic>CASP4<\/jats:italic>\n                      in the autism model compared with controls;\n                      <jats:italic>TLR8<\/jats:italic>\n                      was upregulated in both the hippocampus and peripheral blood, whereas\n                      <jats:italic>CASP4<\/jats:italic>\n                      was upregulated only in the hippocampus. Furthermore, GRN analysis identified miR-891b and miR-627-3p as potential regulators of\n                      <jats:italic>TLR8<\/jats:italic>\n                      , and miR-26b-5p as associated with\n                      <jats:italic>CASP4<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings indicate that\n                      <jats:italic>CASP4<\/jats:italic>\n                      and\n                      <jats:italic>TLR8<\/jats:italic>\n                      , together with their associated regulatory miRNAs, may represent promising biomarkers and potential therapeutic targets for future ASD research and contribute to a better understanding of the pathophysiological mechanisms underlying ASD.\n                    <\/jats:p>\n                  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