Albiflorin-Mediated MAP2K1 Targeting and HIF-1 Signaling Inhibition Contribute to the Therapeutic Efficacy in Hyperuricemia-Associated Cognitive Impairment.

This study investigated the therapeutic effects and mechanisms of Paeonia suffruticosa fruit pod extract (EMP) and its main component albiflorin (AF) on hyperuricemia-associated cognitive impairment (HUA-CI). A HUA-CI mouse model was established, with cognitive function evaluated via Morris water maze. Hippocampal pathology, inflammation, oxidative stress, and apoptosis were assessed using HE staining, ELISA, TUNEL, and Western blotting. Network pharmacology predicted EMP's targets, and molecular docking analyzed AF-MAP2K1 binding. In vitro experiments used UA-stimulated BV2 and HT22 cells to explore AF's effect on HIF-1 signaling. EMP significantly improved cognitive function and reduced pathological damage in the hippocampus of HUA-CI mice. It exerted protective effects by inhibiting inflammatory responses, alleviating oxidative stress, and preventing cell apoptosis. Network pharmacology analysis revealed that EMP acts through multiple targets and pathways, particularly via the strong binding affinity between AF and MAP2K1. Both in vivo and in vitro studies demonstrated that AF inhibited the HIF-1 signaling pathway, thereby reducing microglial activation and associated inflammation, mitigating uric acid-induced neuronal apoptosis, enhancing antioxidant defenses, and protecting neuronal function. Our research indicates that EMP exerts multi-target therapeutic effects on HUA-CI; AF plays a key role by targeting MAP2K1 and inhibiting HIF-1 signaling.