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Agomelatine (AGO), a melatonergic receptor agonist and serotonin 2C antagonist, has demonstrated anti-inflammatory and antioxidant properties. This study aimed to explore the potential of AGO in mitigating BPH induced by testosterone propionate (TP) in rats. Male rats received TP (5\u00a0mg\/kg\/day, subcutaneously) to induce BPH and were pretreated with AGO (80\u00a0mg\/kg\/day) for 28\u00a0days. AGO inhibited the rise in prostate index, serum prostate-specific antigen (PSA), and testosterone levels compared to the BPH-only group. Histological analysis revealed that AGO significantly improved the pathological alterations in prostate tissue architecture when compared to BPH-only group. Furthermore, AGO notably reduced oxidative stress induced by TP, evidenced by a decrease in lipid peroxidation and preserved levels of reduced glutathione. This reduction in oxidative stress led to a decrease in pro-inflammatory cytokines in the prostate, such as Toll-like receptor 4 (TLR4) and interleukin-1 beta (IL-1\u03b2). Additionally, AGO caused a marked decrease in of NLRP3 inflammasome and vascular endothelial growth factor-A (VEGF-A) protein expressions. When compared to the BPH group, AGO\u2019s effects also included a reduction in the immunoexpression of nuclear factor kappa B (NF-\u03baB) and myeloid differentiation primary response 88 (MyD88) proteins. The findings from this study provide new evidence that AGO can alleviate testosterone-induced BPH in rats, likely through the inhibition of the TLR4\/NF\u03baB and NLRP3\/IL-1\u03b2 signaling pathways. These results suggest that AGO could be a promising therapeutic option for managing BPH.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04874-6","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T03:46:04Z","timestamp":1766115964000},"page":"7989-8002","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Protective role of agomelatine via modulation of TLR4\/NF-\u03baB: NLRP3\/IL-1\u03b2 signaling pathways in testosterone-induced benign prostatic hyperplasia in rats"],"prefix":"10.1007","volume":"399","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6184-2901","authenticated-orcid":false,"given":"Asmaa Mohamed","family":"Abdel-Aziz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walaa Yehia","family":"Abdelzaher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nada Amgad","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyaa E.","family":"Abdelkader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasha Fouad","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa Mohamed Mahmoud","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al Shimaa Mahmoud","family":"Kotb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyaa Abdelfattah","family":"Abdelmonaem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"4874_CR1","volume":"889","author":"AM Abdel-Aziz","year":"2020","unstructured":"Abdel-Aziz AM, Gamal El-Tahawy NF, Salah Abdel Haleem MA, Mohammed MM, Ali AI, Ibrahim YF (2020) Amelioration of testosterone-induced benign prostatic hyperplasia using febuxostat in rats: the role of VEGF\/TGF\u03b2 and iNOS\/COX-2. 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