Cerebral Organoid Modeling Reveals That Suppression of Aberrant mTOR Pathway Activation Alleviates Hyperbaric Oxygen-Induced Neurotoxicity

This study established human cerebral organoids as a promising platform for investigating central nervous system oxygen toxicity (CNS-OT). Through integrated transcriptomic, functional, and pharmacological analyses, we demonstrate that hyperbaric oxygen (HBO) exposure triggers pressure-dependent neurotoxicity mediated by the reactive oxygen species (ROS)–lysosome–mechanistic target of rapamycin (mTOR) axis. Key findings include the following: mechanistic hierarchy: Five atmospheres absolute (ATA) HBO induces metabolic dysregulation and cell cycle arrest, whereas six ATA exceeds compensatory thresholds, triggering overt apoptotic signatures; pathway crosstalk: Lysosomal permeabilization activates mTOR complex 1 (mTORC1) via cathepsin release, while mTORC1 hyperactivation suppresses transcription factor EB (TFEB)-mediated lysosomal regeneration, creating a self-amplifying loop; therapeutic potential: Mouse validation confirmed that mTOR inhibition (temsirolimus) attenuates neurotoxicity, with hippocampus-specific efficacy. The cerebral organoid model offers a human-relevant system to overcome species limitations in neurotoxicity research, facilitating mechanistic discovery and therapeutic target identification.