Zhang Zhimin, Yang Jirui, Zhou Qiongli, Zhong Shiyin, Luo Jinghao, Chai Xueting, Liu Jingjing, Zhang Xin, Chang Xuhong, Wang Hui
Department of Toxicology, School of Public Health, Lanzhou University, Gansu, 730000, China.
Department of Toxicology, School of Public Health, Lanzhou University, Gansu, 730000, China.
Redox Biol. 2025 Jul 8;85:103761. doi: 10.1016/j.redox.2025.103761.
Environmental exposure to elevated manganese (Mn) levels is significantly associated with neurocognitive deficits, attracting widespread attention, yet its underlying mechanisms remain incompletely defined. Ferroptosis is recognized as a crucial contributor to cognitive impairments. Our study demonstrates that Mn exposure activates the cGAS-STING pathway, mediating reactive oxygen species (ROS) generation and subsequently inducing apoptosis and ferroptosis. Mechanistically, Mn-induced cGAS-STING activation promotes oxidative stress, characterized by increased ROS and malondialdehyde (MDA) production, alongside diminished glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Furthermore, this activated pathway triggers apoptosis by mediating ROS-dependent alterations in Bax/Bcl-2 expression and Cytochrome C (Cyt C) release from mitochondria. In addition, excessive activation of the cGAS-STING pathway drives ROS accumulation, which impairs iron homeostasis and induces ferroptosis by regulating the expression of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH), and acyl-CoA synthetase long-chain family member 4 (ACSL4). Critically, inhibition of either the cGAS-STING pathway or ROS significantly ameliorated Mn-induced oxidative stress, apoptosis, and ferroptosis. Overall, these findings establish that cGAS-STING pathway activation mediates ROS production, leading to apoptosis and ferroptosis, as an essential mechanism of Mn neurotoxicity. Consequently, targeting the cGAS-STING pathway or ROS represents a promising therapeutic strategy for mitigating Mn neurotoxicity.
环境中暴露于高水平的锰（Mn）与神经认知缺陷显著相关，这引起了广泛关注，但其潜在机制仍未完全明确。铁死亡被认为是认知障碍的关键因素。我们的研究表明，锰暴露激活了cGAS-STING通路，介导活性氧（ROS）的产生，随后诱导细胞凋亡和铁死亡。机制上，锰诱导的cGAS-STING激活促进氧化应激，其特征是ROS和丙二醛（MDA）生成增加，同时谷胱甘肽过氧化物酶（GSH-Px）和超氧化物歧化酶（SOD）活性降低。此外，这种激活的通路通过介导Bax/Bcl-2表达的ROS依赖性改变和线粒体细胞色素C（Cyt C）的释放来触发细胞凋亡。此外，cGAS-STING通路的过度激活驱动ROS积累，通过调节溶质载体家族7成员11（SLC7A11）、谷胱甘肽过氧化物酶4（GPX4）、铁死亡抑制蛋白1（FSP1）、二氢乳清酸脱氢酶（DHODH）和酰基辅酶A合成酶长链家族成员4（ACSL4）的表达来损害铁稳态并诱导铁死亡。至关重要的是，抑制cGAS-STING通路或ROS可显著改善锰诱导的氧化应激、细胞凋亡和铁死亡。总体而言，这些发现表明cGAS-STING通路激活介导ROS产生，导致细胞凋亡和铁死亡，是锰神经毒性的重要机制。因此，靶向cGAS-STING通路或ROS是减轻锰神经毒性的一种有前景的治疗策略。
