Particulate matter 2.5 promotes HIF-1α-associated autophagy and epithelial-mesenchymal transition in 3D retinal pigment epithelial spheroids.

Particulate matter 2.5 (PM2.5) is a major environmental pollutant associated with various systemic disorders, including ocular diseases. Although PM2.5 is known to reach retinal tissues, its effects on retinal pigment epithelial (RPE) cells and the underlying mechanisms remain incompletely understood. In this study, we investigated the effects of PM2.5 exposure on RPE cells using both conventional two-dimensional cultures and a three-dimensional spheroid model, with a focus on hypoxia-inducible factor-1α (HIF-1α)-associated signaling, autophagy, and epithelial-mesenchymal transition (EMT). PM2.5 exposure significantly increased HIF-1α and vascular endothelial growth factor, suggesting activation of hypoxia-like signaling. This was accompanied by the disruption of cell-cell junctions and induction of EMT-related markers, including transforming growth factor-β and matrix metalloproteinases. Mechanistically, PM2.5 activated extracellular signal-regulated kinase (ERK) signaling and promoted autophagy, thereby contributing to EMT progression and cellular damage. Pharmacological inhibition of autophagy using bafilomycin attenuated EMT-related changes and partially restored epithelial integrity in PM2.5-exposed RPE cells, suggesting that autophagy-associated responses may contribute to PM2.5-induced RPE dysfunction. Collectively, these findings provide preliminary mechanistic evidence that PM2.5-induced RPE damage is associated with the coordinated activation of HIF-1α-associated signaling, ERK signaling, and autophagy-associated responses. These pathways may represent potential targets for future investigation aimed at preventing pollution-associated retinal disorders.