cGAS deficiency mitigated PM2.5-induced lung injury by inhibiting ferroptosis.

Abstract

Ferroptosis emerges as one of the pivotal types of cell death during fine particulate matter (PM2.5)-induced lung injury. The recently discovered cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), triggers the activation of the downstream adaptor protein STING by synthesizing cyclic GMP-AMP, playing vital roles in innate immunity and cell death. Nonetheless, the specific function of cGAS in lung injury caused by PM2.5 remains to be elucidated. The present study aimed to explore the involvement of cGAS in the pathogenesis of PM2.5-induced lung injury and its potential mechanisms. The expression levels of cGAS in lung tissues and different types of cells isolated from murine lungs were detected. We generated a PM2.5-induced lung injury model with cGAS conditional knockout mice in type II alveolar epithelial (AT2) cells and investigated the roles of cGAS in ferroptosis in PM2.5-treated AT2 cells. The results demonstrated that PM2.5 could upregulate the expression of cGAS in lung tissues and AT2 cells. cGAS deficiency in AT2 cells not only improved pulmonary function, including lung compliance and oxygen saturation, but also relieved lung pathological injury in mice. In terms of mechanism, the absence of cGAS in AT2 cells notably reduced lipid peroxidation and ferroptosis in lungs exposed to PM2.5, achieved by increasing the protein level of ferritin. Meanwhile, cGAS deficiency also blocked the interaction between NCOA4 and ferritin, thus decreasing ferritinophagy. Additionally, periillaldehyde, one of the cGAS inhibitors, could protect against PM2.5-induced inflammation, oxidative stress, and edema in lung tissues by downregulating cGAS. Overall, cGAS promotes ferroptosis in PM2.5-induced lung injury by enhancing NCOA4-mediated ferritinophagy and shows promise as a therapeutic option for diseases associated with PM2.5 exposure.