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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-\u03b1 (TNF-\u03b1) 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\u2013related 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.<\/jats:p>","DOI":"10.3390\/ijms27094153","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:03:37Z","timestamp":1778144617000},"page":"4153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic Effects of Glycyrrhizic Acid on Dry Eye Disease: Targeting Pyroptosis, Oxidative Stress, and Epithelial Barrier Dysfunction"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4595-3044","authenticated-orcid":false,"given":"Yiran","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1689-506X","authenticated-orcid":false,"given":"Chengxiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital Clinical College, Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0918-2140","authenticated-orcid":false,"given":"Yun","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","article-title":"TFOS DEWS II Definition and Classification Report","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul. 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