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AMP-activated protein kinase (AMPK), an intracellular energy sensor, plays a pivotal role in regulating synaptic integrity and function. Current treatments for ASD exhibit limited benefits in alleviating the core symptoms of ASD. Consequently, we investigated the therapeutic potential of ENERGI, a novel AMPK-activating compound, in a valproate (VPA)-induced mouse model of ASD. ENERGI was administered via drinking water to VPA-induced ASD offspring. After 7\u00a0days of treatment, ENERGI gradually alleviated social defects, repetitive behaviors, and emotional comorbidities in VPA-induced ASD offspring. At the synaptic level, ENERGI treatment restored aberrant plasticity, spine structure, and dendritic arborization in the hippocampus of VPA-induced ASD offspring. Notably, the curative effects of ENERGI in VPA-induced ASD offspring were equivalent to those of D-cycloserine (DCS), a known therapeutic candidate for ASD. Moreover, ENERGI demonstrated superior efficacy in restoring spine abnormalities than DCS. Mechanistically, 7-day ENERGI treatment reversed the reduction in AMPK phosphorylation, and normalized the elevated PSD95 and synaptic GluA2 levels in VPA-induced ASD offspring, whereas DCS treatment only rescued the synaptic GluA2 levels. Overall, these findings suggest that AMPK activation by ENERGI effectively reverses behavioral and synaptic deficits in a preclinical ASD model, supporting AMPK as a promising target for developing novel ASD therapies.<\/jats:p>","DOI":"10.1007\/s12035-025-05533-w","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:24:20Z","timestamp":1764224660000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["AMPK Activation by ENERGI Ameliorates Behavioral and Synaptic Deficits in a Mouse Model of Autism"],"prefix":"10.1007","volume":"63","author":[{"given":"Ming-Chia","family":"Chu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Chun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueh-Jung","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieh-Yu","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Fang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sze-Chi","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Ning","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Jung","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1639-9293","authenticated-orcid":false,"given":"Hui-Ching","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"5533_CR1","doi-asserted-by":"publisher","DOI":"10.1007\/s10803-016-2734-4","author":"JA Christiansz","year":"2016","unstructured":"Christiansz JA, Gray KM, Taffe J, Tonge BJ (2016) Autism spectrum disorder in the DSM-5: diagnostic sensitivity and specificity in early childhood. 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