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Understanding the genetic determinants of MTX efficacy is therefore essential for improving clinical outcomes. However, studies on MTX efficacy\u2013related polymorphisms remain limited, particularly for non-coding variants, for which most evidence is based on statistical associations. Here, through integrative bioinformatics analysis and systematic meta-analysis, we identified rs1544105, a non-coding SNP in the folylpoly-\u03b3-glutamate synthetase (FPGS) gene, as closely associated with MTX efficacy. Compared with the GG genotype, the AA genotype increased disease progression risk (OR: 2.23; 95% CI: 1.16\u20134.30;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.017) and elevated plasma MTX concentration-to-dose ratios at 24\u00a0h (WMD: 2.27; 95% CI: 1.04\u20134.40;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002) and 40\u00a0h (WMC: 0.02; 95% CI: 0.00\u20130.04;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.033). Using prime editing, we generated homozygous mutant (GG) 293T cells, demonstrating that rs1544105 A\u2009&gt;\u2009G increased FPGS expression (~\u20091.5-fold,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05) and intracellular MTX retention (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). Moreover, both cell-based and animal experiments confirmed that rs1544105 A\u2009&gt;\u2009G markedly improved MTX efficacy. Mechanistically, dual-luciferase reporter and electrophoretic mobility shift assays revealed that rs1544105 A\u2009&gt;\u2009G enhanced the binding affinity of the SNP-containing sequence for the transcription factor CREB1, thereby increasing FPGS transcriptional activity and ultimately augmenting MTX efficacy. Our multidimensional study, integrating data analysis with cellular, molecular, and animal experiments, highlights the remarkable regulatory role of a single SNP, rs1544105, in modulating MTX therapeutic response and provides a basis for individualized MTX-based maintenance therapy in ALL patients.\n                  <\/jats:p>","DOI":"10.1186\/s43556-025-00353-9","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T06:38:58Z","timestamp":1763707138000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A single non-coding SNP in FPGS modulates folate drug efficacy in acute lymphoblastic leukemia: data-driven exploration and experimental validation"],"prefix":"10.1186","volume":"6","author":[{"given":"Wenliang","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyue","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoran","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7962-0402","authenticated-orcid":false,"given":"Zichun","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"issue":"1","key":"353_CR1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41572-024-00525-x","volume":"10","author":"L Pagliaro","year":"2024","unstructured":"Pagliaro L, Chen SJ, Herranz D, Mecucci C, Harrison CJ, Mullighan CG, et al. 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