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

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. The authors thank for technical support provided by the teachers of the large instrument platform of the Optometry Hospital of Wenzhou Medical University.

This study was supported by National Natural Science Foundation of China (82201187), National Key Research and Development Program of China (2021YFA1101200), Key Science and Technology Program of Wenzhou (ZY2022021). The funders had no role in study design, data collection and analysis, publication decision, or manuscript preparation. These authors contributed equally: Lanfang Sun, Xiaoyu Ke, Jingjing Yu.

State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, China Lanfang Sun, Xiaoyu Ke, Jingjing Yu, Jinfei Wei, Jiayi Gu, Wanchen Zhou, Yixin Cen, Jin Huang, Xiaoling Zhang, Jiaming Zhang, Shuo Zhang, Xiaojiang Liu, Yangyang Ji, Wentao Yan, Shaohui Pan, Meng Zhou & Wencan Wu Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Eye Hospital, Wenzhou Medical University, Wenzhou, China National Clinical Research Center for Ocular Diseases, Wenzhou Medical University, Wenzhou, China Correspondence to Shaohui Pan, Meng Zhou or Wencan Wu. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.