<p>Autism spectrum disorder (ASD), a neurodevelopmental disorder, is characterized by synaptic dysregulation as its underlying pathophysiological mechanism. 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&#xa0;days 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.</p>