The role and mechanism of the cGAS–STING pathway-mediated ROS in apoptosis and ferroptosis induced by manganese exposure
Zhimin Zhang, Jirui Yang, Qiongli Zhou, Shiyin Zhong, Jinghao Luo, Xueting Chai, Jingjing Liu, Xin Zhang, Xuhong Chang, Hui Wang
Abstract
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. Mn exposure stimulates cGAS to synthesize the second messenger cGAMP, which binds to and activates STING, thereby facilitating the phosphorylation of downstream TBK1 and IRF3, ultimately promoting the expression of type I interferons (I-IFNs). Concurrently, activation of the cGAS–STING pathway induces oxidative stress by enhancing the production of ROS and MDA while reducing the activity of GSH-Px and SOD. Furthermore, the activated cGAS–STING pathway mediates ROS generation, alters the expression of Bax and Bcl-2, and triggers mitochondrial release of Cytochrome C (Cyt C), culminating in apoptosis. Additionally, hyperactivation of the cGAS–STING pathway drives ROS accumulation, which disrupts iron homeostasis and modulates the protein expression of key ferroptosis regulators (SLC7A11, GPX4, FSP1, DHODH, and ACSL4), thereby inducing ferroptosis. • Manganese (Mn) can induce oxidative stress, apoptosis and ferroptosis. • Mn can activate the cGAS–STING pathway and mediate ROS production. • Inhibiting the cGAS–STING pathway and ROS can ameliorate apoptosis and ferroptosis.