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Here, we dissect the circulating immune landscape in POAG patients via high-resolution single-cell RNA sequencing of ~1.4 million peripheral blood mononuclear cells (PBMCs) from 110 patients and 110 controls of Chinese ancestry. We revealed significant immune remodeling in POAG, characterized by increased CD4\n                    <jats:sup>+<\/jats:sup>\n                    T lymphocytes and myeloid cells and impaired cytolytic potential, as evidenced by reduced cell proportions of terminally differentiated CD8\n                    <jats:sup>+<\/jats:sup>\n                    GZMK\n                    <jats:sup>+<\/jats:sup>\n                    T cells and NK cells. Transcriptomic analysis revealed a sophisticated dual transcriptional landscape in which both proinflammatory and neuroprotective signaling pathways coexist across multiple immune cell lineages. While TNF and IFNG pathway genes were broadly downregulated, specific inflammatory activation components and neuroprotective genes were upregulated in distinct cell populations, suggesting that POAG represents a complex immunometabolic syndrome characterized by a dysregulated balance between inflammatory and neuroprotective signaling. Cell type-specific eQTL mapping and SMR analysis revealed that POAG genetic risk loci exert their effects through immune gene regulation in specific PBMC subsets. Functional validation using\n                    <jats:italic>Ifng<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    and\n                    <jats:italic>Tnf<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mice in an LPS\/NMDA-induced retinal injury model, which mirrored the immune alterations observed in human POAG, demonstrated that genetic deficiency in these pathways markedly exacerbated retinal ganglion cell loss and visual pathway deficits. Our study establishes a crucial link between systemic immune dysregulation\u2014specifically the disrupted balance between inflammatory and neuroprotective signaling\u2014and retinal health, highlighting the importance of restoring this balance for future POAG therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1038\/s41392-025-02438-x","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T23:02:42Z","timestamp":1760050962000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Single-cell RNA-seq reveals cell type-specific molecular and genetic associations with primary open-angle glaucoma"],"prefix":"10.1038","volume":"10","author":[{"given":"Huaping","family":"Tian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tujing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiao","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runze","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojue","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruilin","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenglin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"2438_CR1","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1001\/jama.2014.3192","volume":"311","author":"RN Weinreb","year":"2014","unstructured":"Weinreb, R. 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