Walaa H. El-MaadawyEhab HafizSamer A.TadrosSally A. FahimHaidy M. EbrahimMarwa A. FouadYasmin M.Attia2025-06-292025-06-292025-06-20El-Maadawy, W. H., Hafiz, E., Tadros, S. A., Fahim, S. A., Ebrahim, H. M., Fouad, M. A., & Attia, Y. M. (2025). Hydroxychloroquine modulates the progression of experimentally induced benign prostatic hyperplasia in rats via targeting EGFR/ERK/STAT3 and AR/FOXO1/TRAIL pathways: computational and in vivo studies. Scientific Reports, 15(1). https://doi.org/10.1038/s41598-025-04267-yhttps://doi.org/10.1038/s41598-025-04267-yhttps://repository.msa.edu.eg/handle/123456789/6450SJR 2024 0.874 Q1 H-Index 347Benign prostatic hyperplasia (BPH) is a prevalent progressive age-related disorder in men, yet its etiopathophysiology remains poorly understood. Current treatments like finasteride (Fin) have limited long-term efficacy, necessitating alternative therapies. Hydroxychloroquine (HCQ), a safe antimalarial agent, possesses anti-inflammatory, immunomodulatory, and antiproliferative activities, however, its therapeutic effect in BPH has not been investigated. Accordingly, we examined its therapeutic potential and underlying mechanisms, alone or combined with Fin, in testosterone-induced BPH in rats. In BPH-induced rats, HCQ markedly reduced prostate weight and index, and PSA, testosterone, dihydrotestosterone, pro-inflammatory cytokines (TNF-α, κ and IL-6), and the transcription factor “NF-κB” levels, while improving histological abnormalities in epithelial and stromal tissues. HCQ reduced the mRNA expression of AR and ERK1/2, and decreased the protein levels of EGFR and STAT3. Additionally, HCQ increased the mRNA expression of FOXO1 and promoted apoptosis through both intrinsic and TRAIL-mediated pathways. This was evidenced by the upregulation of pro-apoptotic Bax and the downregulation of anti-apoptotic Bcl-2 and Bcl-XL levels in the intrinsic pathway, as well as the reduction in mRNA expression of DR4 and DR5 in the TRAIL-mediated pathway. Notably, combining HCQ with Fin enhanced these effects. Molecular docking revealed HCQ’s strong interactions with androgen receptor (AR), EGFR, ERK1/2, FOXO, and TRAIL death receptors (DR4/DR5), comparable to Fin except for STAT3. Our findings suggest that HCQ modulates BPH progression by targeting STAT3/ FOXO1/TRAIL and EGFR/ERK/AR pathways, offering a promising therapeutic strategy for BPH, either alone or in combination with Fin.en-USBenign prostate hyperplasiaEGFRFOXO1HydroxychloroquineSTAT3TRAIL-mediated apoptosisArticlehttps://doi.org/10.1038/s41598-025-04267-y