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Their role in oral squamous cell carcinoma (OSCC) development remains unexplored. We collected surgically resected cancer and adjacent normal epithelial tissue samples from 67 OSCC cases, and extracted RNA for sequencing after quality control. A genome-wide sQTL analysis was performed using the RNA sequencing data from 67 normal oral epithelial tissue samples. We included peripheral blood DNA samples from 1044 patients with OSCC and 3199 healthy controls to conduct a genome-wide association study. Systematic screening of sQTLs associated with OSCC risk identified a sQTL variant\u2014the rs737540-T allele\u2014independent of eQTLs, significantly associated with an increased risk of OSCC (OR\u2009=\u20091.2,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20096.84\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    ). The rs737540-T allele reduced skipping of EGFR alternative exon 4 by enhancing TAR DNA binding protein (TARDBP) binding to the RNA sequence, leading to increased expression of the longer isoform (\n                    <jats:italic>EGFR-001<\/jats:italic>\n                    ) and reduced expression of the truncated isoform (\n                    <jats:italic>EGFR-004<\/jats:italic>\n                    ). Compared with\n                    <jats:italic>EGFR-004<\/jats:italic>\n                    ,\n                    <jats:italic>EGFR-001<\/jats:italic>\n                    promoted OSCC cell proliferation by reducing ATP-binding cassette subfamily A member 1 (ABCA1) ubiquitination through lower EGFR phosphorylation. ABCA1 was demonstrated to increase the cholesterol content of the plasma membrane via cholesterol efflux, thus affecting membrane fluidity and vimentin-mediated epithelial\u2013mesenchymal transition. An antisense oligonucleotide targeting rs737540 significantly inhibited OSCC proliferation and reversed membrane cholesterol-induced resistance. This study provides novel insights into how genetic variants regulating alternative splicing contribute to OSCC risk and identifies potential therapeutic targets.\n                  <\/jats:p>","DOI":"10.1038\/s41368-025-00402-7","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:01:52Z","timestamp":1768521712000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antisense oligonucleotide targeting TARDBP-EGFR splicing axis inhibits progression of oral squamous cell carcinoma through ABCA1-regulated cholesterol efflux"],"prefix":"10.1038","volume":"18","author":[{"given":"Nan","family":"Ni","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moxu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiran","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jilin","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingqing","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengcheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuancheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5855-2196","authenticated-orcid":false,"given":"Hua","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"402_CR1","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/s41368-023-00249-w","volume":"15","author":"Y Tan","year":"2023","unstructured":"Tan, Y. et al. 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