The cGAS−STING-mediated ROS and ferroptosis are involved in manganese neurotoxicity

Manganese (Mn) has been characterized as an environmental pollutant. Excessive releases of Mn due to human activities have increased Mn levels in the environment over the years, posing a threat to human health and the environment. Long-term exposure to high concentrations of Mn can induce neurotoxicity. Therefore, toxicological studies on Mn are of paramount importance. Mn induces oxidative stress through affecting the level of reactive oxygen species (ROS), and the overabundance of ROS further triggers ferroptosis. Additionally, Mn2+ was found to be a novel activator of the cyclic guanosine-adenosine synthase (cGAS)−stimulator of interferon genes (STING) pathway in the innate immune system. Thus, we speculate that Mn exposure may promote ROS production by activating the cGAS−STING pathway, which further induces oxidative stress and ferroptosis, and ultimately triggers Mn neurotoxicity. This review discusses the mechanism between Mn-induced oxidative stress and ferroptosis via activation of the cGAS−STING pathway, which may offer a prospective direction for future in-depth studies on the mechanism of Mn neurotoxicity.