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SMC1A, a core subunit of the cohesin complex involved in chromatin organization and transcriptional control, has not been fully characterized in HCC. SMC1A expression and prognostic value were analyzed using ICGC and single\u2010cell datasets, and validated in tissue microarrays and clinical specimens. Functional roles were examined in vitro, in vivo, and in patient\u2010derived organoids. Mechanistic studies combined transcriptomic, chromatin, and post\u2010transcriptional analyses to define downstream transcriptional regulation and upstream m6A\u2010dependent control. Therapeutic delivery was assessed using siRNA\u2010loaded LNPs. SMC1A was significantly upregulated in HCC and associated with poor prognosis. SMC1A knockdown suppressed proliferation, migration, invasion, and organoid growth, reduced tumor burden in xenograft and primary models, and promoted apoptosis. Nestin was identified as a transcriptional target of SMC1A; SMC1A facilitated enhancer\u2013promoter interactions to activate Nestin transcription, and Nestin overexpression rescued malignant phenotypes after SMC1A depletion. Upstream, IGF2BP1 bound m6A\u2010modified regions within the SMC1A 3\u2032\u2010UTR, stabilized SMC1A mRNA, and maintained the SMC1A\u2013Nestin axis. Systemic LNP\u2010siSMC1A accumulated in the liver and inhibited tumor growth. SMC1A drives HCC progression through Nestin\u2010associated chromatin regulation and is maintained by IGF2BP1\u2010mediated m6A stabilization. LNP\u2010based silencing of SMC1A suppresses HCC.<\/jats:p>","DOI":"10.1002\/advs.75616","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T08:20:42Z","timestamp":1779438042000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Master Regulator SMC1A, Stabilized by N6\u2010Methyladenosine Reader IGF2BP1, Promotes HCC Progression Through Facilitating Enhancer\u2013Promoter Interaction of Nestin"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6175-7720","authenticated-orcid":false,"given":"Zhenxiang","family":"Peng","sequence":"first","affiliation":[{"name":"Gastroenterology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Chongqing Municipal Health Commission Key Laboratory of Precision Diagnosis and Treatment of Liver Cirrhosis and Complications The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8359-0793","authenticated-orcid":false,"given":"Diguang","family":"Wen","sequence":"additional","affiliation":[{"name":"Gastroenterology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Chongqing Municipal Health Commission Key Laboratory of Precision Diagnosis and Treatment of Liver Cirrhosis and Complications The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Gastroenterology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Chongqing Municipal Health Commission Key Laboratory of Precision Diagnosis and Treatment of Liver Cirrhosis and Complications The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5438-1350","authenticated-orcid":false,"given":"Lin","family":"Lv","sequence":"additional","affiliation":[{"name":"Gastroenterology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Chongqing Municipal Health Commission Key Laboratory of Precision Diagnosis and Treatment of Liver Cirrhosis and Complications The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6997-7180","authenticated-orcid":false,"given":"Shengtao","family":"Liao","sequence":"additional","affiliation":[{"name":"Gastroenterology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Chongqing Municipal Health Commission Key Laboratory of Precision Diagnosis and Treatment of Liver Cirrhosis and Complications The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4792-852X","authenticated-orcid":false,"given":"Wenguang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Gastroenterology Affiliated Banan Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9766-3684","authenticated-orcid":false,"given":"Zhechuan","family":"Mei","sequence":"additional","affiliation":[{"name":"Gastroenterology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Chongqing Municipal Health Commission Key Laboratory of Precision Diagnosis and Treatment of Liver Cirrhosis and Complications The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6234-1068","authenticated-orcid":false,"given":"Chuanfei","family":"Li","sequence":"additional","affiliation":[{"name":"Gastroenterology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"},{"name":"Chongqing Municipal Health Commission Key Laboratory of Precision Diagnosis and Treatment of Liver Cirrhosis and Complications The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"589","article-title":"A Global View of Hepatocellular Carcinoma: Trends, Risk, Prevention and Management","volume":"16","author":"Yang J. 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