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Recent Mendelian randomization and observational analyses support the protective role of SGLT2 inhibition in reducing prostate cancer risk. Additionally, SGLT2 expression in prostate cancer patient samples has been confirmed through immunohistochemistry. The therapeutic potential of empagliflozin, a selective SGLT2 inhibitor, in treating prostate cancer, either alone or with chemotherapeutic agents like docetaxel, remains largely unexplored. This study investigated the cytotoxic and synergistic effects of empagliflozin in combination with docetaxel in LNCaP and DU- 145 prostate cancer cells. Cell viability was assessed using the MTT assay, and synergy was evaluated using the Chou-Talalay method. Western blot analysis was conducted to examine the effects of empagliflozin, alone and in combination with docetaxel, on key molecular targets, including p-AMPK\u03b1, p-p70S6 K1, p-PRAS40, and p-Akt. Empagliflozin exhibited concentration-dependent cytotoxic effects in both LNCaP and DU- 145 cells, with a higher potency observed in DU- 145 cells. When combined with docetaxel, empagliflozin demonstrated synergistic activity, as indicated by combination index values &lt;\u20091. Empagliflozin upregulated p-AMPK\u03b1 and downregulated p-p70S6 K1 and p-PRAS40. The combination with docetaxel further enhanced these effects. Notably, empagliflozin alone downregulated p-Akt in LNCaP cells but not in DU- 145 cells, highlighting cell-line-specific differences. Empagliflozin reduces prostate cancer cell viability and enhances the cytotoxic effects of docetaxel, suggesting a promising combination strategy for prostate cancer therapy. Additional in vivo studies and clinical trials are needed to assess the translational relevance of these findings.<\/jats:p>","DOI":"10.1007\/s00210-025-04132-9","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T06:57:23Z","timestamp":1744613843000},"page":"13819-13831","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effects of empagliflozin and its combination with docetaxel on LNCaP and DU- 145 prostate cancer cell lines: cytotoxicity and molecular pathway analysis"],"prefix":"10.1007","volume":"398","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3997-7746","authenticated-orcid":false,"given":"Ahmet","family":"Cumao\u011flu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8372-4806","authenticated-orcid":false,"given":"Selda Nur","family":"Akdeniz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0208-3086","authenticated-orcid":false,"given":"Ahmad","family":"Karzoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9320-0583","authenticated-orcid":false,"given":"Mohamed","family":"Alaama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4503-8032","authenticated-orcid":false,"given":"M\u00fckerrem Bet\u00fcl","family":"Yerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"4132_CR1","doi-asserted-by":"publisher","first-page":"112455","DOI":"10.1016\/j.biopha.2021.112455","volume":"145","author":"AM Abdelhamid","year":"2022","unstructured":"Abdelhamid AM, Saber S, Youssef ME, Gaafar AG, Eissa H, Abd-Eldayem MA et al (2022) Empagliflozin adjunct with metformin for the inhibition of hepatocellular carcinoma progression: Emerging approach for new application. 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