Previous stereotactic-electroencephalography (SEEG) results have suggested that seizure-onset zones (SOZs) could be suppressed by strengthened inward connectivity from the rest of the brain during interictal periods, which might explain why people with epilepsy did not have seizures continuously. However, the limited coverage of SEEG contacts and allocation bias hindered a more comprehensive survey of interictal suppression at the whole-brain level. Previous studies also lacked a direct comparison between patients and healthy controls due to the invasive nature of SEEG. In the present study, we introduced metabolic connectivity mapping (MCM), a simultaneous FDG-PET/fMRI-based measure of effective connectivity, to evaluate the inward and outward connectivity of the SOZs in patients with mesial temporal lobe epilepsy (MTLE). Specifically, simultaneous FDG-PET/fMRI data was acquired from 23 patients with left MTLE, 24 patients with right MTLE, and 25 healthy controls. At the whole-brain level, there was significant increase of inward MCM connectivity to the SOZs, which mostly came from mesial-temporo-limbic, anterior and posterior midline regions of the default mode network (DMN) and subcortical nuclei. There was also significant decrease of outward MCM connectivity from the SOZs, which mainly projected to the regions within DMN. The increased net inward MCM to the SOZs, calculated by subtracting outward MCM from the inward MCM, was positively correlated with seizure frequency. Within DMN, MTLE patients showed decreased MCM from the SOZs to posterior cingulate cortex and right ventromedial prefrontal cortex and increased effective connectivity from posterior cingulate cortex to the SOZs. Based on the MCM patterns within DMN, we were able to classify the epileptic side of MTLE with an accuracy of 91.67% (79.17% for MRI-negative patients). Overall, our results provide whole-brain evidences for the interictal suppression hypothesis. We also found that the regions within DMN play a critical role in the suppression of SOZs. The pattern of such suppressive network might also serve as potential features for the localization of SOZs. Our neuroimaging results does not only provide a comprehensive understanding of interictal suppression at the whole-brain level, but also shed lights on a non-invasive and time-efficient way for SOZs localization.Copyright © 2025. Published by Elsevier Inc.