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

Xiaoying Ma; Ye Bai; Jiahui He; Yunxia Guo; Miao Meng; Sergey M. Novikov; Valentyn S. Volkov; Ilya Zavidovskiy; Dianhuai Meng; Yan Huang; Xiaochen Bao; Xiangwei Zhao

doi:10.1016/j.eng.2025.10.020

Engineering ›› DOI: 10.1016/j.eng.2025.10.020

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

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Abstract

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.

Keywords

Cerebral organoid / Central nervous system oxygen toxicity / Hyperbaric oxygen therapy / Mammalian target of rapamycin pathway / Transcriptome sequencing

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Xiaoying Ma, Ye Bai, Jiahui He, Yunxia Guo, Miao Meng, Sergey M. Novikov, Valentyn S. Volkov, Ilya Zavidovskiy, Dianhuai Meng, Yan Huang, Xiaochen Bao, Xiangwei Zhao. Cerebral Organoid Modeling Reveals That Suppression of Aberrant mTOR Pathway Activation Alleviates Hyperbaric Oxygen-Induced Neurotoxicity. Engineering DOI:10.1016/j.eng.2025.10.020

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