GLP-1R agonist semaglutide protects developing human forebrain organoids from cholesterol-induced neurotoxicity—scRNA sequence

The GLP-1R agonist semaglutide is well-established for improving systemic lipid profiles and is gaining attention for its clinical neuroprotective potential; however, the mechanisms underlying its direct action on neural cells remain poorly understood. Using hiPSC-derived forebrain organoids, we modeled cholesterol-induced metabolic stress to investigate direct drug-cell interactions.

We show that semaglutide protects neural cells from lipotoxic injury. Intracellularly, GLP-1R activation engages the cAMP-PKA and PI3K-AKT-mTOR signaling, contributing to the reduction of lipid droplet and ROS levels. Intercellularly, single-cell transcriptomics indicates that semaglutide partially reestablishes disrupted cellular communication, including the Midkine signaling network associated with progenitor support.