Water-insoluble components of PM2.5 are major triggers of pulmonary ferroptosis by inducing mitochondrial damage via Nrf2/Prdx6 pathway.

Fine particulate matter (PM2.5) is a major environmental pollutant that poses a significant risk to respiratory health. Ferroptosis represents a key pathogenic mechanism underlying this process. However, the relative contributions of specific PM2.5 components and the potential mechanisms through which they induce pulmonary ferroptosis remain unclear. This study aimed to compare pulmonary ferroptosis triggered by PM2.5 components and to elucidate the underlying mechanisms via in vivo and in vitro experiments. The cytotoxicity of PM2.5 exposure on BEAS-2B cells was measured through the CCK-8 assay. The mitochondrial ultrastructural alterations were assessed by transmission electron microscopy (TEM). The levels of ferroptosis-related markers were quantified by qRT-PCR and Western blot. The results indicated that PM2.5 exposure caused mitochondrial damage in mouse lungs, and cellular experiments further revealed water-insoluble components (WICs) as the primary contributors to such damage. Consistently, after exposure to different components of PM2.5, WICs were more potent than water-soluble components (WSCs) in inducing Fe2 +release, ROS production, MDA release, GSH depletion, and alterations in ferroptosis-related markers. Notably, Nrf2 inhibition markedly sensitized cells to PM2.5-induced ferroptosis, whereas Prdx6 overexpression effectively mitigated this effect. Our results demonstrated that WICs were identified as the primary components responsible for PM2.5-induced ferroptosis, mediated by disruption of the Nrf2/Prdx6 pathway. These findings offer new insights into the environmental health risks of PM2.5 and establish the Nrf2/Prdx6 axis as a potential therapeutic target for air pollution-related pulmonary diseases.