Perfluorooctane sulfonate (PFOS) induces Caspase-8-mediated pyroptosis via GSDMD and GSDME to drive retinal disease: Evidence from epidemiological and experimental studies.

While perfluorooctane sulfonate (PFOS) has been epidemiologically associated with ocular disorders, its direct specific role in retinal disease and the underlying molecular mechanisms are still not well understood. We initially examined serum PFAS levels in relation to retinal diseases among 777 participants (666 controls vs. 111 cases) from the Isomer of C8 Health Project in China. Then, C57BL/6 mice were orally gavaged with PFOS at doses of 0.8, 8, and 80 μg/kg/day for 90 days in vivo. The retinal ganglion cell line (RGC-5) was also exposed to PFOS at concentrations of 0, 1, 10, and 100 μM for 24 h in vitro. Epidemiological analysis showed a significant positive association between serum PFOS levels and the risk of retinal disease (OR = 1.46, 95%CI: 1.20, 1.80). In mice, exposure to PFOS caused progressive retinal thinning, retinal ganglion cell (RGC) loss, and retinal inflammation. In RGC-5 cells, PFOS activated Caspase-8, which led to cleavage of both GSDMD and GSDME, thereby inducing pyroptosis. Blocking Caspase-8 significantly reduced pyroptotic cell death involving GSDMD or GSDME. This study identifies PFOS as a new environmental trigger for retinal diseases through Caspase-8-mediated dual cleavage of GSDMD and GSDME. Our findings connect human exposure data with mechanistic toxicology and highlight the Caspase-8-gasdermin axis as a potential therapeutic target for PFOS related retinal disease.