lncRNA Pvt1 promotes retinal ischemia-reperfusion injury by modulating the PPM1B/RIPK3 pathway through promoter methylation.

Retinal ischemia-reperfusion (I/R), a hallmark feature of many retinal degenerative diseases, often leads to irreversible neuronal damage. Among the various forms of cell death, necroptosis has emerged as a pivotal mechanism contributing to retinal neurodegeneration. Here, we identify a novel regulatory axis that modulates neuronal necroptosis using the long non-coding RNA (lncRNA) Pvt1. Using both in vitro (R28 cell line) and in vivo (intravitreal injection of adeno-associated virus carrying lncRNA Pvt1 shRNA in rats) models, the role of lncRNA Pvt1 under I/R in vivo and oxygen-glucose deprivation/reperfusion (OGD/R) in vitro is assessed. Comprehensive molecular and cellular analyses show that I/R or OGD/R induce robust necroptotic responses in neuronal cells. Notably, lncRNA Pvt1 knockdown significantly alleviates these necroptotic phenotypes by inhibiting RIPK3 phosphorylation. Mechanistically, lncRNA Pvt1 knockdown reduces Ppm1b promoter methylation, restoring PPM1B expression. Subsequently, PPM1B protein upregulation facilitates RIPK3 dephosphorylation, effectively dampening the necroptosis signaling cascade. These findings reveal that the previously unrecognized lncRNA Pvt1/PPM1B/p-RIPK3 axis is essential for neuronal survival following ischemic stress. This study provides compelling evidence that targeting the lncRNA Pvt1 is a promising therapeutic strategy for mitigating retinal neuronal necroptosis. Modulating this pathway provides new opportunities for the treatment of I/R-related retinal diseases.