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Dysregulation of folate intake and metabolism is strongly implicated in the pathogenesis of hepatocellular carcinoma (HCC). Although small nucleolar RNAs (snoRNAs) have shown promise as diagnostic and prognostic biomarkers in HCC, the impact of folate deficiency on their expression landscape remains uncharacterized. Here, by performing snoRNA-seq in folate-deficient HepG2 cells, we systematically identified 26 differentially expressed snoRNAs for the first time. Functional enrichment analysis indicated that downregulated snoRNAs were closely associated with cell proliferation pathways. From these, we selected SNORD1B, highly expressed in HCC tissues, correlated with poor prognosis, and significantly suppressed upon 28-day FA deprivation for mechanistic investigation. We demonstrated that FA deficiency coordinately downregulated SNORD1B and its host gene SNHG16 (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05), with strong positive correlation (R\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.5104,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0465). This downregulation led to markedly reduced 2\u2032-O-methylation at the G4362 site of 28S rRNA (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.01) and impaired ribosomal activity. Expression of snoRNA-binding proteins (FBL, NOP58, NOP56) as well as IL-6 and CDK1 were significantly suppressed (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05), alongside decreased TP53 protein levels (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). Functional assays confirmed that FA deficiency potently inhibited HepG2 proliferation and migration (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.01). Our findings reveal a previously unrecognized mechanism: folate deficiency attenuates SNORD1B-dependent 2\u2032-O-methylation of 28S rRNA, resulting in ribosomal dysfunction and suppression of global protein synthesis, thereby inhibiting HCC cell proliferation and migration. This study provides novel insight into the epigenetic-ribosomal axis of FA-mediated tumor suppression and highlights snoRNAs as potential therapeutic targets in HCC.\n                  <\/jats:p>","DOI":"10.1186\/s41065-026-00666-x","type":"journal-article","created":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T23:34:58Z","timestamp":1774222498000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Folate-driven changes in snoRNA function: a novel epigenetic-ribosomal axis in hepatocellular carcinoma"],"prefix":"10.1186","volume":"163","author":[{"given":"Xinxin","family":"Song","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyu","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjiao","family":"Zi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"666_CR1","doi-asserted-by":"publisher","first-page":"3508","DOI":"10.3390\/cancers15133508","volume":"15","author":"S Chamseddine","year":"2023","unstructured":"Chamseddine S, LaPelusa M, Kaseb AO. Systemic neoadjuvant and adjuvant therapies in the management of hepatocellular carcinoma-a narrative review. Cancers (Basel). 2023;15:3508.","journal-title":"Cancers (Basel)"},{"key":"666_CR2","doi-asserted-by":"publisher","first-page":"e943","DOI":"10.1016\/S2468-2667(23)00211-6","volume":"8","author":"J Qi","year":"2023","unstructured":"Qi J, Li M, Wang L, Hu Y, Liu W, Long Z, et al. National and subnational trends in cancer burden in China, 2005\u201320: an analysis of national mortality surveillance data. Lancet Public Health. 2023;8:e943\u201355.","journal-title":"Lancet Public Health"},{"key":"666_CR3","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1038\/s41417-024-00764-w","volume":"31","author":"F Safri","year":"2024","unstructured":"Safri F, Nguyen R, Zerehpooshnesfchi S, George J, Qiao L. Heterogeneity of hepatocellular carcinoma: from mechanisms to clinical implications. 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