Anti-inflammatory and Metabolic Regulatory Effects of Ocular-Accumulative Phenolic Compounds in Dry Eye Disease Management

Dry eye disease (DED), characterized by symptoms of dryness and inflammation in the eyes, has become a prevalent ocular disorder worldwide. While several DED medications are available, their effectiveness is often limited by the low bioavailability and rapid clearance from ocular tissues. Alternatively, phenolic compounds with ocular-targeting and anti-inflammatory properties provide viable solutions. This study aimed to explore the ability of polyphenols to reach ocular tissues and exert therapeutic effects against dry eye symptoms in <em>in vivo</em> and <em>in vitro</em> models. The therapeutic mechanisms of ocular-accumulative phenolic compounds were further investigated in a human corneal epithelial cell (HCEC) model of DED. For <em>in vivo</em> studies, db/db mice were administrated to a polyphenol-rich herbal preparation (PHP), followed by assessments of dry eye symptoms, and identification of ocular accumulative phenolic compounds through targeted metabolomics. For<em> in vitro</em> studies, HCECs were exposed to a hyperosmolar solution to induce DED, followed by evaluation of the ability of selected phenolic compounds to maintain cell viability and attenuate inflammation. For mechanistic investigation, metabolomics and lipidomics were performed on samples prepared using the innovative enhanced matrix removal (EMR)-lipid µelution technique alongside assessments on gene expression and molecular interactions through molecular docking analyses. Results show that PHP treatment significantly improved corneal surface integrity and reduced inflammation in mice. Among the phenolic metabolites detected in ocular tissues, urolithin A (UA) and 3,4-dihydroxybenzoic acid (3,4-diHBA) exhibited the strongest anti-inflammatory effects in the DED cell model, as evinced by the downregulated interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels. Furthermore, integrated metabolomic and lipidomic analyses revealed significant differences in multiple metabolite levels and metabolic pathways across groups. Of note, 3,4-diHBA and UA remarkably regulated amino acid metabolism, glutathione metabolism, sphingolipid and glycerophospholipid metabolic pathways, which may collectively support restoration of cellular metabolic functions related to anti-inflammation, ocular surface integrity maintenance, and osmoregulation. Overall, this study highlights the therapeutic potential of diet-derived, ocular-accumulative phenolic compounds in the management of DED.&nbsp;