本研究建立了人脑类器官作为研究中枢神经系统氧中毒（CNS-OT）的可靠模型。通过整合转录组学、功能学及药理学分析，我们揭示高压氧（HBO）暴露可通过ROS-溶酶体-mTOR轴引发压力依赖性的神经毒性。主要发现如下：在毒性机制的分级效应上，5 ATA（绝对大气压）HBO可引起代谢失调与细胞周期阻滞，而6 ATA则突破代偿极限，导致明显的凋亡特征；在信号通路的交叉调控上，溶酶体膜通透性增加促使组织蛋白酶释放，进而激活mTORC1，而mTORC1的过度活化会抑制TFEB介导的溶酶体再生，由此形成自我放大的恶性循环；在治疗潜力方面，小鼠体内实验证实，mTOR抑制剂替西罗莫司（temsirolimus）可减轻神经毒性，且对海马区具有特异性保护作用。该脑类器官模型提供了一个贴近人体的实验系统，可突破神经毒性研究中的物种限制，有助于推动机制研究和治疗靶点的发现。

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.