Identifying a role for oxytosis/ferroptosis in Pde6b-associated retinitis pigmentosa

Inherited retinal diseases (IRDs) are a large heterogeneous group of diseases that lead to visual impairment and complete vision loss. Retinitis pigmentosa (RP) is an IRD with progressive degeneration of photoreceptors and has been associated with mutations in over 80 genes. In this study, we investigated the mechanism of retinal degeneration caused by an inherited mutation in the Pde6b gene in the rd10 mouse model of RP, with a focus on alternative programmed cell death pathways. RNA-seq analysis was used to identify changes in gene expression in rd10 mice, using C57BL/6J mice as non-degenerating genetic background controls. The functional role of differentially expressed genes was investigated using pharmacological treatments and visual acuity was assessed using optomotor kinetic tracking assay. We found increased expression of genes involved in inflammatory response, while expression of genes involved in photoreceptor function and homeostasis were decreased. We also demonstrated increased expression of genes that regulate oxytosis/ferroptosis, a type of regulated necrosis that can promote inflammatory responses. We found no significant changes in expression of genes controlling other types of regulated necrosis. Treating rd10 mice with oxytosis/ferroptosis inhibitors led to significant improvements in visual acuity. Therefore, these findings suggest that disruption of Pde6b activity results in photoreceptor death via oxytosis/ferroptosis, contributing to inflammatory responses in the retina. Our results identify for the first time a possible role of oxytosis/ferroptosis in a model of inherited retinal degeneration and provide a foundation for further studies exploring oxytosis/ferroptosis inhibitors as a potential therapeutic strategy for RP.