Z-DNA-Binding Protein 1 Knockdown Attenuates Photoreceptor Cell Death after Retinal Detachment in Association with Reduced Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Signaling and PANoptosis-Related Pathway Activation.

Retinal detachment (RD) is caused by the separation of the neural retina from the retinal pigment epithelium, which leads to photoreceptor cell death as the main cause of vision loss. Here, this study investigated the role of Z-DNA-binding protein 1 (ZBP1)-mediated PANoptosis in photoreceptor death after RD and elucidated its interaction with the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Initially, up-regulation of ZBP1 expression in the vitreous fluid of patients with retinal detachment was detected, and retinal detachment mouse models were subsequently established via surgery. Western blot analysis and immunofluorescence confirmed a significant up-regulation of ZBP1 expression on day 3 after RD, accompanied by PANoptosis and cGAS-STING pathway activation. To investigate its mechanism, ZBP1 expression was knocked down via subretinal injection of adeno-associated virus serotype 9-shRNA-Zbp1, which was found to reduce the expression of core PANoptosis molecules and inhibit the activity of the cGAS-STING signaling. Subsequently, hematoxylin and eosin staining, transmission electron microscopy, and electroretinography confirmed that ZBP1 knockdown improved retinal morphology, partially restored outer nuclear layer thickness and retinal function, and reduced photoreceptor cell death. Similarly, i.p. injection of the cGAS-STING inhibitor C-176 attenuated ZBP1 activation and alleviated PANoptosis. In summary, ZBP1 regulates photoreceptor PANoptosis following RD, with knockdown alleviating this process via reduced cGAS-STING signaling and PANoptosis-related pathway activation.