A circRNA-microRNA-Pdcd1 axis drives microglial activation and retinal ganglion cell degeneration

Abstract Retinal ganglion cell (RGC) degeneration is the primary cause of vision loss, driven by the complicated effects of intrinsic neuronal damage and neuroinflammation. However, current single-target therapies fail to address these dual pathological challenges. CircRNAs, functioning through ceRNA networks, represent a multi-target intervention due to their stability. Here we show that, using whole‑transcriptome sequencing of optic nerve crush (ONC), we bioinformatically predicted nine candidate ceRNA networks. Among these, the network centered on circAgtpbp1 was significantly up-regulated post-injury, independent of its host gene. Mechanistically, circAgtpbp1 functions as a ceRNA by sequestering miR-3098-3p, thereby de-repressing the translation of PD-1 ( Pdcd1 ). In the ONC model, this upregulation of PD-1 protein amplifies microglial activation, creating a pathogenic non-cell-autonomous inflammatory amplification loop that drives RGC degeneration. Our findings not only uncover a novel circRNA-mediated mechanism in neurodegeneration but also identify the circAgtpbp1-miR-3098-3p-Pdcd1-microglia axis as a promising therapeutic target for neuroprotective interventions.