Honokiol (HNK) accelerates corneal epithelial wound healing by promoting HMGCS2-mediated mitochondrial metabolic...

Corneal epithelial regeneration is critical for restoring ocular surface function after injury. This study investigated the therapeutic potential and molecular mechanism of honokiol (HNK) in promoting corneal epithelial repair. Using a murine corneal epithelial debridement model, we observed that HNK accelerated wound healing and upregulated KRT12 and Ki67 expression in injured corneas. In vitro, HNK significantly enhanced proliferation and migration of human corneal epithelial cells (HCE-T), as demonstrated by CCK-8 and scratch assays. Bulk RNA sequencing identified differentially expressed genes following HNK treatment, and subsequent bioinformatics analysis highlighted the mitochondrial enzyme 3-hydroxymethylglutaryl CoA synthetase 2 (HMGCS2) as a key mediator. HMGCS2, the mitochondrial isoform of 3-hydroxy-3-methylglutaryl-CoA synthase, serves as a critical regulatory node in lipid-derived ATP production and ketogenesis. Gene interference and mitochondrial activity assays confirmed that HNK promotes corneal epithelial repair by targeting HMGCS2 and enhancing mitochondrial function. These findings suggest that HNK facilitates corneal wound healing through a mitochondria-dependent mechanism, offering a potential therapeutic strategy for ocular surface regeneration.