This study investigates whether activation of LRP1 can ameliorate LPS-induced cognitive deficits by recalibrating cerebral glucose metabolism.<h4>Methods</h4>We utilized an integrative approach combining behavioral phenotyping with targeted metabolomics and transcriptomics to dissect the neuroprotective mechanism of SP16, a selective LRP1 agonist. Here, LRP1 is linked to Cognitive impairment.