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

Particulate matter 2.5 (PM_2.5) is a major environmental pollutant associated with various systemic disorders, including ocular diseases. Although PM_2.5 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 PM_2.5 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). PM_2.5 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, PM_2.5 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 PM_2.5-exposed RPE cells, suggesting that autophagy-associated responses may contribute to PM_2.5-induced RPE dysfunction. Collectively, these findings provide preliminary mechanistic evidence that PM_2.5-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.