Lipocalin 2 as a novel target of pralatrexate mitigating corneal epithelial damage in a mouse model of herpes simplex keratitis.

Herpes simplex keratitis (HSK), a sight-threatening ocular infection caused by herpes simplex virus (HSV), primarily induces blindness through corneal damage driven by the lytic death of infected epithelial cells. Only a limited number of antiviral agents are approved for HSK management, highlighting an urgent need to explore novel anti-HSK agents. At present, the antifolate agent pralatrexate (PDX), originally developed as an anti-tumor agent, demonstrates robust anti-HSV-1 activity both in vitro and in vivo, including ACV-resistant strain HSV-1/153. Moreover, PDX treatment also alleviates HSV-1-induced corneal epithelial damage and inflammation progression. We identified a previously unexplored novel mode of action for PDX against HSV-1. Mechanistically, PDX suppresses lipocalin-2 (LCN2) expression by reducing P65 phosphorylation and inhibiting its nuclear translocation, which may be involved in HSV-1 replication inhibition and corneal inflammation progression reduction. In conclusion, our work highlights PDX as a promising anti-HSK agent, given its efficacy against viral replication and corneal epithelial damage via inhibiting LCN2 expression.