Nobiletin mitigates benign prostatic hyperplasia by suppressing prostate cell proliferation through regulation of cell cycle progression, signaling pathways, transcription factor activity, and the androgen-signaling axis

Background and aim Benign prostatic hyperplasia (BPH) involves androgen-driven proliferation with reduced apoptosis. Current 5α-reductase inhibitors can cause adverse effects, motivating safer options. We evaluated whether nobiletin, a polymethoxyflavonoid, mitigates BPH features. Methodology In vitro , nobiletin was applied to BPH-1 epithelial and WPMY-1 stromal cells to assess anti-proliferative effects. In vivo efficacy was tested in a testosterone-induced BPH rat model administered oral nobiletin (1 or 5 mg/kg). Results Nobiletin induced G0/G1 phase cell cycle arrest by suppressing cyclin D1, cyclin E, and cyclin-dependent kinase 2 (CDK2), while elevating p21 and p27 expression. Expression of 5α-reductase, androgen receptor (AR), fibroblast growth factor (FGF), epidermal growth factor (EGF), and B-cell lymphoma 2 (Bcl-2) was reduced, whereas Bcl-2–associated X protein (Bax) was increased. Nobiletin modulated phosphorylation of c-Jun N-terminal kinase (JNK) and p38 and suppression of protein kinase B (AKT) phosphorylation. Nobiletin reduced nuclear factor kappa B (NF-κB) DNA-binding activity, which was dependent on JNK and p38. In vivo , nobiletin reduced prostate size, weight, and epithelial thickness, accompanied by molecular markers changing in the same direction as in vitro . Molecular docking analysis further supported the potential of nobiletin to bind 5α-reductase type 2 at the catalytic site. Conclusion These results highlight the potential of nobiletin as a novel therapeutic option for BPH.