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We employed Oxford Nanopore long-read sequencing to analyze the full-length transcriptome of human aortic smooth muscle cells after CSE treatment. We confirmed that low-concentration CSE (0.2%) slightly promoted cell viability while higher concentrations (0.4%\u22120.8%) induced dose-dependent suppression. Sequencing of 0.6% CSE (midpoint cytotoxicity)-treated cells revealed 11,222 novel transcripts and extensive post-transcriptional reprogramming, including: 1,866 upregulated transcripts involving ferroptosis and cell division; 493 downregulated transcripts in oxidative phosphorylation and glutathione metabolism; 1,753 alternative polyadenylation events mediating 3\u2019UTR remodeling; and 269 alternative splicing events affecting cell cycle regulators and transcription factors (CREM, FOSL1, HBP1). Our study suggests that high-concentration CSE cytotoxicity is executed through coordinated post-transcriptional dysregulation, providing the first isoform-level perspective on smoking-induced vascular pathology and revealing previously unrecognized regulatory mechanisms in cigarette smoke-mediated vascular injury.<\/jats:p>","DOI":"10.1371\/journal.pone.0354604","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:01:29Z","timestamp":1790013689000},"page":"e0354604","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A comprehensive full-length transcriptome landscape of cigarette smoke-exposed HASMCs reveals extensive remodeling of mRNA isoforms and regulatory networks"],"prefix":"10.1371","volume":"21","author":[{"given":"Wei","family":"Gou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulin","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3927-058X","authenticated-orcid":true,"given":"Zhipeng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"issue":"2","key":"pone.0354604.ref001","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/S0025-7125(16)30354-6","article-title":"Trends in cigarette smoking in the United States. 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