Master Regulator SMC1A, Stabilized by N6‐Methyladenosine Reader IGF2BP1, Promotes HCC Progression Through Facilitating Enhancer–Promoter Interaction of Nestin

ABSTRACT HCC remains a leading cause of cancer‐related mortality, and effective therapies are limited. 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‐cell datasets, and validated in tissue microarrays and clinical specimens. Functional roles were examined in vitro, in vivo, and in patient‐derived organoids. Mechanistic studies combined transcriptomic, chromatin, and post‐transcriptional analyses to define downstream transcriptional regulation and upstream m6A‐dependent control. Therapeutic delivery was assessed using siRNA‐loaded 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–promoter interactions to activate Nestin transcription, and Nestin overexpression rescued malignant phenotypes after SMC1A depletion. Upstream, IGF2BP1 bound m6A‐modified regions within the SMC1A 3′‐UTR, stabilized SMC1A mRNA, and maintained the SMC1A–Nestin axis. Systemic LNP‐siSMC1A accumulated in the liver and inhibited tumor growth. SMC1A drives HCC progression through Nestin‐associated chromatin regulation and is maintained by IGF2BP1‐mediated m6A stabilization. LNP‐based silencing of SMC1A suppresses HCC.