Invest Ophthalmol Vis Sci. 2026 Jul 1;67(8):63. doi: 10.1167/iovs.67.8.63.
ABSTRACT
PURPOSE: Herpes simplex keratitis (HSK) is a leading cause of infectious corneal blindness. Host antiviral responses, particularly type I interferon (IFN) signaling, are impaired during corneal herpes simplex virus type 1 (HSV-1) infection, partly due to viral immune evasion and metabolic reprogramming. This study investigated if topical glycolysis inhibition restores mitochondrial antiviral signaling (MAVS)-associated innate antiviral signaling and improves HSK outcomes.
METHODS: In vitro and in vivo infection models were established using the HSV-1 McKrae strain. A stable hexokinase 2 (HK2)-knockdown human corneal epithelial cell (HCEC) line was generated using lentivirus. Protein/mRNA levels were analyzed via western blot (WB), immunofluorescence (IF), enzyme linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR). Protein interactions were confirmed by co-immunoprecipitation (Co-IP). Murine corneal pathology and viral proteins were assessed by slit-lamp imaging, IF, and WB.
RESULTS: Elevated HK2 expression was detected in HSK models. HK2 knockdown or 2-deoxy-d-glucose (2-DG)-mediated inhibition reduced HSV-1 replication (lower infected cell protein 0 [ICP0], higher interferon-stimulated gene 56 [ISG56]). Co-IP confirmed the interaction between HK2 and MAVS protein, and HK2 inhibition activated the TANK-binding kinase 1 (TBK1)/interferon regulatory factor 3 (IRF3) pathway. Topical application of 2-DG improved murine corneal epithelial integrity, reduced viral proteins (glycoprotein D, ICP0), and showed efficacy comparable to acyclovir.
CONCLUSIONS: Topical glycolysis inhibition enhances corneal antiviral defenses via MAVS-mediated type I IFN signaling, controlling HSV-1 and alleviating disease. It reveals a novel corneal metabolism-antiviral immunity link, highlights HK2 as a therapeutic target for HSK, and supports metabolic therapies for HSK and ocular herpes virus infections.
PMID:42530913 | DOI:10.1167/iovs.67.8.63