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<p>Prostate carcinoma remains a predominant contributor to cancer-associated morbidity in males, with rising prevalence and therapeutic resistance highlighting unmet clinical needs. Ferroptosis—a non-apoptotic cell death mechanism mediated through iron-catalyzed phospholipid peroxidation—has emerged as a promising strategy to circumvent drug-resistant malignancies. We investigated the mechanistic interplay between transferrin receptor 1 (TfR1) and borax-mediated ferroptotic activation in androgen-responsive and androgen-independent prostate adenocarcinoma models. Cytotoxic effects of borax on LNCaP and DU-145 cells were assessed using CCK-8 and BrdU assays across 2.5&#xa0;μM to 320&#xa0;μM concentrations over 24–72&#xa0;h. Expression and levels of TfR1, GPX4, ACSL4, GSH, MDA, total ROS, and intracellular Fe<sup>2</sup>⁺ were evaluated through ELISA, Western blotting, and RT-PCR. Ferroptosis specificity was confirmed using ferrostatin-1 inhibition studies and exclusion of apoptosis/necroptosis/autophagy by pharmacological inhibitors. Nuclear alterations and superoxide anion production were examined using DAPI staining. IC₅₀ values were 138&#xa0;μM (95% CI: 115–153&#xa0;μM) for LNCaP cells and 92.1&#xa0;μM (95% CI: 83.4–102&#xa0;μM) for DU-145 cells, with DU-145 demonstrating higher sensitivity. Borax exposure in DU-145 cells decreased GSH and GPX4 levels while increasing MDA, ROS, Fe<sup>2</sup>⁺, ACSL4, and TfR1 expression. Ferrostatin-1 pretreatment effectively attenuated these effects, confirming ferroptosis-dependent mechanisms. Nuclear abnormalities and elevated superoxide production were observed. These findings demonstrate that borax induces cytotoxicity in prostate cancer cells through ferroptosis via TfR1/GPX4/ACSL4 cascade modulation, suggesting a potential role for TfR1 in governing ferroptotic vulnerability. While high concentrations limit immediate clinical application, these results establish mechanistic foundations for ferroptosis-targeted therapy development in prostate cancer.</p>

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Borax Triggers Ferroptosis by Modulating the TfR1/GPX4/ACSL4 Pathway in Prostate Cancer Cells with Differential Androgen Sensitivity

  • 期刊论文

  • 发表日期：

    2025年10月7日

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  • Ekrem Basaran,
  • Ceyhan Hacioglu,
  • Dursun Baba,
  • Arda Taşkın Taşkıran,
  • Ahmet Yıldırım Balık

摘要

Prostate carcinoma remains a predominant contributor to cancer-associated morbidity in males, with rising prevalence and therapeutic resistance highlighting unmet clinical needs. Ferroptosis—a non-apoptotic cell death mechanism mediated through iron-catalyzed phospholipid peroxidation—has emerged as a promising strategy to circumvent drug-resistant malignancies. We investigated the mechanistic interplay between transferrin receptor 1 (TfR1) and borax-mediated ferroptotic activation in androgen-responsive and androgen-independent prostate adenocarcinoma models. Cytotoxic effects of borax on LNCaP and DU-145 cells were assessed using CCK-8 and BrdU assays across 2.5 μM to 320 μM concentrations over 24–72 h. Expression and levels of TfR1, GPX4, ACSL4, GSH, MDA, total ROS, and intracellular Fe2⁺ were evaluated through ELISA, Western blotting, and RT-PCR. Ferroptosis specificity was confirmed using ferrostatin-1 inhibition studies and exclusion of apoptosis/necroptosis/autophagy by pharmacological inhibitors. Nuclear alterations and superoxide anion production were examined using DAPI staining. IC₅₀ values were 138 μM (95% CI: 115–153 μM) for LNCaP cells and 92.1 μM (95% CI: 83.4–102 μM) for DU-145 cells, with DU-145 demonstrating higher sensitivity. Borax exposure in DU-145 cells decreased GSH and GPX4 levels while increasing MDA, ROS, Fe2⁺, ACSL4, and TfR1 expression. Ferrostatin-1 pretreatment effectively attenuated these effects, confirming ferroptosis-dependent mechanisms. Nuclear abnormalities and elevated superoxide production were observed. These findings demonstrate that borax induces cytotoxicity in prostate cancer cells through ferroptosis via TfR1/GPX4/ACSL4 cascade modulation, suggesting a potential role for TfR1 in governing ferroptotic vulnerability. While high concentrations limit immediate clinical application, these results establish mechanistic foundations for ferroptosis-targeted therapy development in prostate cancer.