Work

Quercetin Disrupts Nuclear Factor Erythroid 2–related Factor 2 Survival Signaling and Activates a Pro-apoptotic Microrna Program in Acute Myeloid Leukemia

Year: 2026

Type: article

Abstract: Background Nuclear factor erythroid 2–related factor 2 (NRF2) promotes antioxidant defense but, when constitutively activated in malignant cells, can support survival and therapy resistance. We previously demonstrated that quercetin induces apoptosis in leukemia through epigenetic modulation. Here, we investigated an additional mechanism linking NRF2 regulation to apoptosis-related microRNAs in acute myeloid leukemia (AML). Aim To determine how quercetin modulates NRF2 signaling and whether NRF2 suppression is functionally associated with pro-apoptotic microRNA responses in AML. Materials and Methods: HL-60 and U937 cells, primary CD34+ cells from untreated AML patients, and HL-60/U937 xenografts in NOD/SCID mice were studied. NRF2 expression, subcellular localization, ubiquitin association, and proteasome-dependent degradation were assessed by Western blotting, confocal microscopy, and imaging flow cytometry. Reactive oxygen species (ROS) were measured by flow cytometry. Apoptosis-related microRNAs were screened by PCR array and validated by RT-qPCR. Functional studies included stable NRF2 silencing, apoptosis and viability assays, and ectopic miR-206 expression. Results Quercetin significantly reduced NRF2 protein levels in both AML xenograft models. In leukemia cells, quercetin decreased NRF2 and phosphorylated NRF2, restricted NRF2 nuclear localization, and increased ubiquitin-associated signal; proteasome inhibition with MG132 restored NRF2 accumulation, supporting proteasome-dependent degradation. Reduced nuclear NRF2 and increased ubiquitin association were also observed in primary CD34+ AML cells. Quercetin decreased HDAC4 and increased intracellular ROS in HL-60 and U937 cells (p<0.05). In vivo, quercetin altered 16 of 84 apoptosis-related microRNAs, with significant upregulation of miR-1, miR-133a, miR-133b, and miR-206 (p<0.05). NRF2 silencing increased miR-206 expression (p<0.05) and sensitized U937 cells to quercetin-induced apoptosis (p<0.05) and loss of viability (p<0.001). Conversely, ectopic miR-206 expression reduced NRF2 (p<0.001) and BCL2 (p<0.05) protein levels. Discussion These findings support two converging mechanisms: post-translational suppression of NRF2 signaling and activation of a pro-apoptotic microRNA program, with miR-206 functionally linked to NRF2 and BCL2 regulation. Conclusion Quercetin disrupts NRF2-dependent survival responses in AML by restricting nuclear localization, promoting proteasome-dependent degradation, and increasing oxidative stress. The functional interplay between NRF2 suppression and miR-206 identifies a regulatory vulnerability associated with enhanced apoptotic sensitivity and supports NRF2 modulation as a potential therapeutic strategy in AML.

Source: Hematology Transfusion and Cell Therapy

DOI: 10.1016/j.htct.2026.107669