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

Theodor Bilharz Research Institute

Bibliographic Information

Authors: El-Maadawy W.H.; Hafiz E.; Tadros S.A.; Fahim S.A.; Ebrahim H.M.; Fouad M.A.; Attia Y.M.

Journal: Scientific Reports

Publisher: Nature Research

Publication Date: 20 June 2025

Volume / Issue: Volume 15 / Issue 1

Article No.: 20118

ISSN: 20452322

DOI: 10.1038/s41598-025-04267-y

Scopus: View on Scopus

PubMed: 40541965

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

El-Maadawy W.H., Pharmacology Department, Theodor Bilharz Research Institute, P.O. box 30, Warrak El-Hadar, Imbaba, Giza, 12411, Egypt; Hafiz E., Electron Microscopy Department, Theodor Bilharz Research Institute, P.O. box 30, Warrak El-Hadar, Imbaba, Giza, 12411, Egypt; Tadros S.A., Department of Biochemistry, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), P.O. Box 12451, 26 July Mehwar Road Intersection with Wahat Road, 6th of October City, Cairo, Egypt; Fahim S.A., Department of Biochemistry, School of Pharmacy, Newgiza University (NGU), P.O. Box 12577, Newgiza, km 22 Cairo-Alexandria Desert Road, Giza, Egypt; Ebrahim H.M., Animal House Unit, National Cancer Institute, Cairo University, Kasr Al Eini Street, Fom El Khalig, Cairo, Egypt; Fouad M.A., Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Newgiza University (NGU), Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt, Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, P.O. Box 11562, Kasr El-Aini St., Cairo, Egypt; Attia Y.M., Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Kasr Al Eini Street, Fom El Khalig, Cairo, Egypt

Abstract

Benign 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. © The Author(s) 2025.

Keywords

Benign prostate hyperplasia; EGFR; FOXO1; Hydroxychloroquine; STAT3; TRAIL-mediated apoptosis; Animals; Apoptosis; Disease Models, Animal; Disease Progression; ErbB Receptors; Finasteride; Forkhead Box Protein O1; Male; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Signal Transduction; STAT3 Transcription Factor; Testosterone; TNF-Related Apoptosis-Inducing Ligand; androgen receptor; Egfr protein, rat; epidermal growth factor receptor; Foxo1 protein, rat; STAT3 protein; Stat3 protein, rat; transcription factor FKHR; tumor necrosis factor related apoptosis inducing ligand; animal; disease exacerbation; disease model; drug effect; drug therapy; genetics; metabolism; pathology; prostate hypertrophy; rat; Sprague Dawley rat

Citation Information

Scopus Citations: 2

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