Hexokinase‐2 as a Therapeutic Target: Alleviating Herpes Simplex Keratitis Through Metabolic Reprogramming

Abstract Herpes simplex keratitis (HSK) is a leading infectious cause of blindness worldwide, with current therapies primarily targeting viral replication rather than addressing host‐cell injury. RNA sequencing of corneal tissue from HSK patients and healthy donors identifies a metabolic shift from mitochondrial oxidative phosphorylation to aerobic glycolysis. Notably, hexokinase‐2 (HK2), a pivotal glycolytic enzyme, exhibits the greatest up‐regulation, coinciding with a marked reduction in the activity of mitochondrial respiratory chain complexes in HSK corneas. Pharmacological inhibition of HK2 with lonidamine in human corneal epithelial cells reduces herpes simplex virus type 1 (HSV‐1) replication while preserving cell viability. In a murine model of HSK, topical lonidamine restored respiratory‐chain activity, lowered viral load, and accelerated corneal re‐epithelialization; its early therapeutic efficacy surpassed that of ganciclovir, and combination therapy conferred additive benefit. These findings identify HK2‐driven glycolytic reprogramming as a pathogenic hallmark of HSK and demonstrate that metabolic targeting concurrently restricts viral propagation and promotes tissue regeneration. Thus, metabolic intervention has the potential to complement direct antiviral therapy and represents a promising, clinically translatable strategy to preserve vision in HSK.