SIRT3 mitigates dry eye disease through the activation of autophagy by deacetylation of FOXO1.

Dry eye disease (DED) is a complex ocular condition characterized by oxidative stress, inflammation, and apoptosis. An increasing number of studies suggest that Sirtuin3 (SIRT3), a mitochondrial deacetylase, may offer protection against related pathologies. Despite these indications, the precise function and underlying mechanisms of SIRT3 in the context of DED have not been fully elucidated. Here, we observed a decline in SIRT3 expression in human corneal epithelial cells (HCE-Ts) and the corneal conjunctiva of mice as the disease advanced. Overexpression of SIRT3 in HCE-Ts reduced the accumulation of reactive oxygen species (ROS), inflammatory cytokines, and the rate of apoptosis, while its inhibition had the opposite effect. Importantly, the function of SIRT3 was exerted through the enhancement of autophagic flux. Further studies have shown that chloroquine-induced inhibition of autophagy neutralized the beneficial effects of SIRT3. In our in vivo experiments, the application of eye drops containing a SIRT3 agonist ameliorated the symptoms of DED and increased corneal autophagy in mice. Mechanistically, our study identified that the deacetylation and nuclear translocation of FOXO1 (Forkhead box O1) are pivotal for the SIRT3-mediated enhancement of autophagic flux. These findings posit that SIRT3 as an encouraging therapeutic target for DED, offering new insights into the disease's underlying mechanisms.