Dual impact of EZH1/2-targeted therapy in HTLV-1-associated inflammation: Direct and indirect mechanisms

Abstract

Human T cell leukemia virus type 1 (HTLV-1)-associated inflammation, including uveitis, lacks effective targeted therapies. Here, we investigated whether epigenetic modulation through EZH1/2 inhibition could influence HTLV-1-related ocular inflammation using in vitro co-culture and infection models. HTLV-1 exposure increased EZH1 and EZH2 expression and the repressive histone mark H3K27me3 in retinal pigment epithelial cells. Treatment with the dual EZH1/2 inhibitor valemetostat reduced H3K27me3 levels. Valemetostat showed limited effects on cell viability and induced only modest, context-dependent apoptosis. Virological analyses showed model-dependent changes in proviral load, accompanied by reduced viral gene expression. Profiling of cytokines and chemokines revealed context-dependent modulation of inflammatory mediators. Functional assessment using p65 nuclear translocation assays indicated partial attenuation of NF-κB activation under inflammatory stimulation. Collectively, these findings suggest that EZH1/2-mediated epigenetic regulation is primarily involved in HTLV-1-related inflammatory responses, and that inhibiting EZH1/2 may be a potential approach to modulate inflammatory signaling.