Abstract

Dry eye disease (DED) is a prevalent ocular surface disorder in which current therapies fail to achieve complete symptomatic relief. Given the pivotal role of excessive reactive oxygen species (ROS) in the vicious cycle of DED, effective strategies for ROS elimination remain urgently needed. Herein, a superoxide anion (O 2 · − )-responsive persulfide prodrug, Ac-SOPD, is designed for DED treatment. This prodrug specifically responses to O 2 · − to generate persulfides, which subsequently react with cysteine to trigger sustained hydrogen sulfide (H 2 S) release. The released H 2 S, a critical gasotransmitter, further scavenges residual ROS and bolsters endogenous antioxidant defenses. Mechanistically, Ac-SOPD efficiently eliminates excessive ROS, rejuvenates mitochondrial function, and inhibits the overactivation of the Hippo pathway, thereby preventing apoptosis. In both evaporative and aqueous-deficient DED models, Ac-SOPD significantly reduces oxidative stress, inflammation, and apoptosis on the ocular surface, thus alleviating corneal epithelial damage and improving tear film stability. Collectively, our findings demonstrate that Ac-SOPD holds strong potential for the treatment of DED and other oxidative stress-related diseases.