PI3K/Akt Signaling as a Potential Therapeutic Target for Reducing Inflammation and Corneal Stromal Injury in Microsporidial Stromal Keratitis

Purpose: This study aimed to investigate the role of the PI3K/Akt pathway in microsporidial stromal keratitis (MSK) and evaluate whether targeted inhibition of this pathway could provide a potential therapeutic strategy. Methods: A mouse model of MSK was established, followed by transcriptomic analysis to identify gene-expression changes following microsporidial infection. The activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was assessed through real-time quantitative polymerase chain reaction (RT-qPCR), immunostaining, and protein phosphorylation assays. To explore therapeutic implications, the PI3K/Akt inhibitor LY294002 was administered by subconjunctival injection, and its effects on corneal inflammation and cytokine production were assessed over the course of infection. Results: Microsporidial infection markedly activated the PI3K/Akt pathway in the cornea, as evidenced by increased phosphorylation of PI3K and Akt. Transcriptomic analysis revealed upregulation of inflammatory cytokines, including MMP9, IL-1β, and TNF-α, indicating activation of inflammation-related pathways. Histologic analysis further confirmed increased immune cell infiltration and stromal edema in infected corneas. Pretreatment with LY294002 prior to infection alleviated the clinical manifestations of MSK, including corneal opacity, and reduced corneal expression of inflammatory expression levels, suggesting a contributory role of PI3K/Akt pathway in the pathogenesis and inflammation of MSK. Conclusions: PI3K/Akt signaling is a critical driver of inflammation in MSK. Targeting this pathway may present a promising strategy for the management of MSK. Future studies should focus on developing ocular-optimized inhibitors of the PI3K/Akt pathway and evaluating their safety and efficacy for potential clinical application in MSK treatment.