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Immune evasion driven by defective antigen presentation and CD8\u207a T cell dysfunction is a hallmark of hepatocellular carcinoma (HCC). This study aimed to determine whether NRGN contributes to immune escape in HCC and to elucidate its underlying molecular mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>NRGN expression and clinical relevance were analyzed in public datasets and validated in HCC tissues. Transcriptomic and enrichment analyses assessed antigen presentation. Gain- and loss-of-function experiments were performed in human and murine HCC cells, while orthotopic and subcutaneous models with CD8\u207a T cell exhaustion, \u03b22M knockout, and H-2Kb blockade evaluated immune dependence in vivo. RNA stability, RNA pulldown, RIP, co-immunoprecipitation, ubiquitination, and luciferase assays were conducted to define the molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NRGN was significantly upregulated in HCC and associated with advanced stage and poor survival, correlating inversely with GZMB\u207a CD8\u207a T cell infiltration. NRGN knockdown enriched MHC-I antigen presentation pathways and restored MHC-I\/\u03b22M expression, tumor cell surface antigen presentation, and CD8\u207a T cell cytotoxicity. In vivo, NRGN silencing suppressed tumor growth and prolonged survival in a CD8\u207a T cell-dependent manner, effects reversed by \u03b22m deletion or H-2Kb blockade. Mechanistically, NRGN downregulated IRF8 by reducing its mRNA stability through FMR1 and stabilizing FMR1 protein via inhibition of MYCBP2-mediated ubiquitination, thereby sustaining suppression of antigen presentation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NRGN suppresses antigen presentation via the FMR1-IRF8-MHC-I axis, thereby impairing CD8\u207a T cell-specific effector functions and promoting immune evasion in HCC. Modulation of the NRGN\u2013IRF8\u2013MHC-I axis could represent a potential strategy for improving immunotherapeutic responses.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03783-7","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T11:24:29Z","timestamp":1784114669000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NRGN inhibits CD8\u207a T cell effector function by downregulating MHC-I expression through the FMR1\u2013IRF8 axis in hepatocellular carcinoma"],"prefix":"10.1186","volume":"45","author":[{"given":"Dongjie","family":"Ye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiacheng","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinqiao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7495-5254","authenticated-orcid":false,"given":"Nanhong","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"issue":"3","key":"3783_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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