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<p>Triple-negative breast cancer (TNBC) presents significant clinical challenges due to its aggressive nature and limited treatment options. This study investigates the anticancer potential of β-sitosterol (SIT) compared to doxorubicin (DOX), focusing on <i>miR-21</i>-<i>3p</i> suppression and apoptosis pathway modulation in MDA-MB-231 cells.MDA-MB-231 cells were treated with SIT (6.25–100 µM) or DOX (0.1µM). Assessments included MTT viability assay, Annexin V/PI apoptosis detection, cell cycle analysis, qRT-PCR, Western blot, and oxidative stress markers. Computational analyses involved molecular docking and 200-ns molecular dynamics simulations. SIT dose-dependently reduced cell viability (IC50 = 39.56 µM), comparable to DOX. SIT preferentially induced early apoptosis (30.7%) while DOX triggered late apoptosis (49%). Both compounds caused G1 phase arrest. SIT upregulated Cleaved Caspase-3 (2.8-fold) and AMPK (2.4-fold) while downregulating GSK3β (0.6-fold) and mature <i>miR-21-3p</i> (0.6 fold). Oxidative stress analysis revealed SIT reduced malondialdehyde by 64.7% and increased total antioxidant capacity by 12.6-fold. Docking showed binding energies of -7.88&#xa0;kcal/mol (SIT) and − 8.44&#xa0;kcal/mol (DOX) to <i>pre-miR-21</i>. Molecular dynamics confirmed superior stability of the SIT-<i>pre-miR-21</i> complex (RMSD: 0.445&#xa0;nm). β-sitosterol appears to exert its anticancer activity through <i>pre-miR-21</i> binding, AMPK/Caspase-3 activation, and oxidative stress reduction. Although doxorubicin demonstrated greater potency, β-sitosterol showed comparable efficacy with superior antioxidant properties. This study provides novel structural insights into SIT’s direct targeting of <i>pre-miR-21</i>, positioning it as a promising therapeutic candidate for TNBC. However, these findings from a single cell line model require validation in additional TNBC models and in vivo systems.</p> Graphical Abstract <p></p>

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Targeting pre-miR-21 with β-Sitosterol to Inhibit miR-21-3p Maturation in Triple-Negative Breast Cancer: Structural and Comparative Insights with Doxorubicin

  • 期刊论文

  • 发表日期：

    2026年4月25日

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  • Sholeh Javadi,
  • Somayeh Farahmand,
  • Reza HajiHosseini,
  • Sima Nasri

摘要

Triple-negative breast cancer (TNBC) presents significant clinical challenges due to its aggressive nature and limited treatment options. This study investigates the anticancer potential of β-sitosterol (SIT) compared to doxorubicin (DOX), focusing on miR-21-3p suppression and apoptosis pathway modulation in MDA-MB-231 cells.MDA-MB-231 cells were treated with SIT (6.25–100 µM) or DOX (0.1µM). Assessments included MTT viability assay, Annexin V/PI apoptosis detection, cell cycle analysis, qRT-PCR, Western blot, and oxidative stress markers. Computational analyses involved molecular docking and 200-ns molecular dynamics simulations. SIT dose-dependently reduced cell viability (IC50 = 39.56 µM), comparable to DOX. SIT preferentially induced early apoptosis (30.7%) while DOX triggered late apoptosis (49%). Both compounds caused G1 phase arrest. SIT upregulated Cleaved Caspase-3 (2.8-fold) and AMPK (2.4-fold) while downregulating GSK3β (0.6-fold) and mature miR-21-3p (0.6 fold). Oxidative stress analysis revealed SIT reduced malondialdehyde by 64.7% and increased total antioxidant capacity by 12.6-fold. Docking showed binding energies of -7.88 kcal/mol (SIT) and − 8.44 kcal/mol (DOX) to pre-miR-21. Molecular dynamics confirmed superior stability of the SIT-pre-miR-21 complex (RMSD: 0.445 nm). β-sitosterol appears to exert its anticancer activity through pre-miR-21 binding, AMPK/Caspase-3 activation, and oxidative stress reduction. Although doxorubicin demonstrated greater potency, β-sitosterol showed comparable efficacy with superior antioxidant properties. This study provides novel structural insights into SIT’s direct targeting of pre-miR-21, positioning it as a promising therapeutic candidate for TNBC. However, these findings from a single cell line model require validation in additional TNBC models and in vivo systems.

Graphical Abstract