Dual Targeting of MiRNA-21 and PI3K/AKT by Honokiol Overcomes Paclitaxel Resistance in Triple-Negative Breast Cancer

Background Triple-negative breast cancer (TNBC) is aggressive and frequently develops paclitaxel resistance. The oncomiR miRNA-21 promotes chemoresistance by targeting PTEN and PDCD4. Honokiol, a natural lignan, modulates miRNAs and enhances chemosensitivity. This study investigated whether honokiol sensitizes TNBC cells to paclitaxel via the miRNA-21/PTEN/PI3K/AKT axis. Methods MDA-MB-231 and MDA-MB-468 cells were treated with honokiol, paclitaxel, or their combination at IC ₅₀ doses. Cytotoxicity was assessed by MTT and combination index (CI) analysis. Proliferation, migration, colony formation, apoptosis, and gene/protein expression were evaluated using trypan blue, wound healing, colony formation, Hoechst/ELISA/caspase-3, qRT-PCR, and Western blotting. Results Honokiol and paclitaxel synergistically reduced cell viability (CI < 1), with IC ₅₀ values decreasing from 6.22 to 4.21 µM (MDA-MB-231) and 5.03 to 3.21 µM (MDA-MB-468). Combination suppressed migration (to 44.5% and 32.5%) and colony formation (29% and 31%). Honokiol downregulated miRNA-21, and upregulated PTEN/PDCD4, were reversing paclitaxel-induced miRNA-21 elevation. Combination reduced phospho-AKT, cyclin D1, and MMP-2. Apoptosis was enhanced (caspase-3: 2.46 and 2.62 fold). Conclusions Honokiol overcomes paclitaxel resistance in TNBC by modulating miRNA-21/PTEN/PI3K/AKT signaling, offering a promising combination strategy.