Resveratrol Modulates lncRNA Expression Profiles in Leukemia Stem Cell Line

Objective: Leukemia stem cells (LSCs) are central to therapy resistance and disease relapse. Long non-coding RNAs (lncRNAs) act as key epigenetic regulators whose dysregulation sustains leukemic stemness. This study aimed to evaluate whether resveratrol, a natural polyphenol, can selectively modulate the lncRNA expression landscape in LSCs compared with healthy hematopoietic stem cells (HSCs).Materials and Methods: Human LSC and healthy HSC lines were treated with 16.7 µM resveratrol for 72 hours. Differential expression of 90 lncRNAs was assessed using quantitative real-time PCR. RNA–protein interaction networks and functional enrichment analyses were performed using the RAIN database integrated with the STRING consortium.Results: Resveratrol markedly reprogrammed the LSC transcriptome, resulting in the upregulation of nine and downregulation of nineteen lncRNAs. Notably, expression of the tumor suppressor anti-NOS2A was restored (5.70-fold), a molecule previously identified as strongly suppressed in LSCs. Significant induction was also observed for PTENP1 (6.15-fold) and LincRNA-SFMBT2 (8.30-fold), while oncogenic lncRNAs HOTTIP (−11.34-fold), SNHG5 (−8.99-fold), and MALAT1 (−7.61-fold) were strongly inhibited. In contrast, healthy HSCs exhibited a substantially attenuated transcriptional response, indicating high selectivity of resveratrol toward leukemic stem cells. Network analysis further associated upregulated lncRNAs with pathways related to JAK–STAT signaling and apoptotic regulation.Conclusion: Resveratrol functions as a selective epigenetic modulator in leukemia stem cells by restoring tumor-suppressive lncRNA signatures while silencing oncogenic drivers. These findings support the potential of resveratrol as a complementary strategy to target LSC-mediated resistance while sparing normal hematopoiesis.