Particulate matter 2.5 stimulates pyroptosis and necroptosis via the p38 MAPK/Akt/NF-κB signaling pathway in human corneal epithelial cells

Abstract

Particulate matter 2.5 (PM2.5) exposure poses significant health risks, particularly to the eyes. This study aimed to investigate the cytotoxic effects of PM2.5 on human corneal epithelial cells (HCECs) and to elucidate the mechanisms involved in pyroptosis and necroptosis. HCECs were exposed to PM2.5, and cytotoxicity, reactive oxygen species (ROS) levels, and the expression of pyroptosis- and necroptosis-related proteins were assessed. The roles of nuclear factor-kappa B (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signaling pathways were also investigated. Exposure to PM2.5 caused a dose-dependent decrease in cell viability, accompanied by significant NLRP3 inflammasome activation, leading to pyroptosis and the release of pro-inflammatory cytokines. Enhanced ROS generation and mitochondrial dysfunction have also been observed, along with indicators of necroptosis, such as increased levels of mixed-lineage kinase domain-like proteins. Importantly, activation of the NF-κB signaling pathway was crucial for these responses. The suppression of p38 mitogen-activated protein kinase (MAPK) and activation of protein kinase B (Akt) using pharmacological modulators SB203580 and SC79, respectively, significantly reduced PM2.5-mediated cellular damage. These findings indicate that p38 MAPK inhibition and Akt activation are key regulatory mechanisms that help attenuate the deleterious effects of PM2.5 on HCECs. In conclusion, our findings offer new insights into the mechanisms by which PM2.5 induces pyroptosis and necroptosis in HCECs, especially by activating the NLRP3 inflammasome and NF-κB signaling pathways. The critical regulatory roles of p38 MAPK and Akt underscore their potential as therapeutic targets to alleviate PM-induced ocular damage. © 2025 Elsevier B.V.