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

Neurological disorders are increasingly linked to disrupted lipid metabolism. 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. Functionally, semaglutide mitigates excitotoxicity and stabilizes calcium dynamics. In summary, these findings highlight the importance of cholesterol homeostasis during early brain development and suggest that GLP-1R signaling may represent a candidate neuroprotective axis in the central nervous system, offering insights into therapeutic strategies for neurological disorders.