Ferroptosis is involved in the damage of ocular lens under long-term PM2.5 exposure in rat models and humans

Epidemiological studies show a positive association between air pollution and age-related cataracts, but the pathogenic mechanism remains unclear. This study first demonstrates that fine particulate matter (PM_2.5) induces ferroptosis in the lens, leading to morphological and functional disorders, through human, animal, and cellular samples. In 3-week PM_2.5-exposed rat models (10 µl 1 mg/ml PM_2.5 suspension per eye, 4 times a day), we find that many vacuoles form in the lens equatorial region by analysis of haematoxylin and eosin staining after PM_2.5 exposure. Using iron and glutathione (GSH) assay kits, we found increased Fe²⁺ contents and decreased GSH levels in PM_2.5-exposed rats' lenses. Additionally, the lipid peroxide 4-hydroxynonenal (4-HNE) was also found to be elevated with immunoblot, suggesting ferroptosis is involved. Ferroptosis was also observed in human lens epithelial cells treated with 25, 50, and 100 µg/ml PM_2.5 suspension for 24 h, accompanied by decreased cell viability and migration. Furthermore, we collect about 60 human lens anterior capsule (HLAC) samples for RNA-seq. The results show that compared to HLACs from areas with PM_2.5 concentration ≤30 μg/m³, ferroptosis-related genes expression of those from areas with PM_2.5 concentration ≥35 μg/m³ are significantly altered, such as glutathione peroxidase 4 and STEAP family member 3. Also, human lens in areas with high PM_2.5 concentrations showed elevated levels of transferrin receptor and 4-HNE with immunoblot, and down-regulated expression of connexin 43 (Cx43) through immunofluorescent. These results demonstrate that ferroptosis plays a key role in PM_2.5-induced cataractogenesis.