Therapeutic Effects of Glycyrrhizic Acid on Dry Eye Disease: Targeting Pyroptosis, Oxidative Stress, and Epithelial Barrier Dysfunction.

Dry eye disease (DED) is a common ocular surface disorder characterized by instability of the tear film, inflammatory responses, and epithelial damage, and therapeutic interventions directed at these fundamental pathogenetic processes are still insufficient. This research aimed to evaluate the medicinal efficacy of glycyrrhizic acid (GA) and to unravel the underlying molecular pathways through which it exerts its protective role in DED. A benzalkonium chloride-induced mouse model and a hyperosmolarity-induced human corneal epithelial cell model were established. Corneal epithelial injury, tear secretion, and goblet cell density were evaluated in vivo, while cellular responses and related signaling pathways were examined using RT-qPCR, Western blotting, flow cytometry, and immunofluorescence. GA treatment alleviated corneal epithelial damage, increased tear secretion, and improved goblet cell density in mice. In vitro, GA reduced inflammatory responses, as evidenced by decreased tumor necrosis factor-α (TNF-α) expression, and helped preserve epithelial barrier integrity, accompanied by reduced matrix metalloprotease 9 (MMP9) levels. Further analysis suggested that GA suppressed pyroptosis through regulation of the high mobility group box 1 (HMGB1)/lysosomal membrane permeabilization (LMP)/cathepsin B (CTSB) pathway and attenuated oxidative stress via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/NAD (P)H:quinone oxidoreductase 1 (NQO1) axis. In addition, GA improved mitochondrial function, as indicated by decreased reactive oxygen species levels, restored membrane potential, and enhanced adenosine triphosphate (ATP) production. Taken together, these findings indicate that GA may alleviate hyperosmolarity-induced DED by modulating inflammation, oxidative stress, mitochondrial dysfunction, and epithelial barrier damage, underscoring its viability as a remedial candidate.