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Recent studies have suggested that vitamin D (VitD) supplementation play a role in reducing the risk of ASD and alleviating some of its core symptoms. However, variations in individual responses to VitD due to biological heterogeneity have led to inconsistent clinical outcomes, and the precise molecular mechanisms through which VitD might exert its effects on ASD remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the effects of calcitriol, the biologically active form of VitD, on ASD\u2010associated phenotypes in BTBR mice, a well\u2010established autism model. Behavioral assessments were used to evaluate social and repetitive behaviors. Mechanistic insights were obtained through RNA sequencing, immunohistochemistry, biochemical assays, and stripe guidance assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Calcitriol supplementation significantly improved autism\u2010like behaviors in BTBR mice, alleviating hippocampal hypoplasia and correcting axon guidance abnormalities. These effects were mediated by modulation of the EfnA4\u2010PI3K signaling pathway in hippocampal neural progenitor cells and other brain regions, highlighting its role in neurodevelopmental processes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings demonstrate that calcitriol targets axon\u2010guidance\u2010related signaling pathways, providing a theoretical framework and potential clinical strategy for targeted ASD interventions.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70429","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T03:51:04Z","timestamp":1747799464000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Calcitriol Modulates Hippocampal Axon Guidance Through Enhanced <scp>EfnA4<\/scp>\u2010Mediated <scp>PI3K<\/scp>\/<scp>AKT<\/scp> Signaling in an Autism Mouse 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