Histone methyltransferase inhibitors prevent lens opacity in diabetic cataract rats.

OBJECTIVE: To investigate the effect and mechanism of histone methylation on galactose-induced lens opacity. METHODS: Lenses from SD rats were cultured in 30 mM galactose medium to induce opacification, with intervention using four histone methyltransferase inhibitors (GSK126, Pinometostat, GSK3326595, BIX-01294). Lens opacity, structural changes (HE staining/transmission electron microscopy (TEM)), differentially expressed genes (high-throughput sequencing), and validated targets (qPCR) were analyzed. A diabetic cataract (DC) rat model was established via intraperitoneal galactose injection, with BIX-01294 intervention. Ocular lesions (fundus/slit-lamp examination), lens structure (HE staining), AR/TNF-α levels (ELISA), and Pikfyve mRNA expression (qPCR) were assessed. Ex vivo, YM201636 (a Pikfyve inhibitor) was used to intervene in galactose-induced opacity, with opacity observation and structural evaluation (HE staining/TEM). RESULTS: The four histone methyltransferase inhibitors ameliorated lens opacity to varying degrees. HE staining and TEM results showed that histone methyltransferase inhibitors alleviated lens injury, with BIX-01294 exhibiting the most pronounced effect. High-throughput sequencing of the model group and the BIX-01294 intervention group revealed that after BIX-01294 treatment, 113 genes were upregulated and 60 genes were downregulated. qPCR validation showed that mRNA expression levels of Pth1r, Fam111a, Pikfyve, and H19 were significantly downregulated after BIX-01294 intervention. Furthermore, BIX-01294 intervention reduced lens injury, decreased AR activity and TNF-α content, and lowered Pikfyve mRNA expression in DC rats. Intervention with YM201636 (a Pikfyve inhibitor) alleviated galactose-induced lens opacity and improved lens damage in vitro. CONCLUSION: Histone methyltransferases are involved in lens opacity in DC rats by regulating Pikfyve gene expression.