ArticleJournal of nanobiotechnology2025
Metformin-amplified ferroptosis induced by ultrasmall manganese ferrite nanoparticles: a GPX4-independent strategy for prostate cancer therapy.
Article in Journal of nanobiotechnology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Nanomaterial-based ferroptosis inducers hold potential to overcome limitations of conventional cancer therapies, though most rely on glutathione peroxidase 4 (GPX4) downregulation. However, downregulation of GPX4 can impair the tumor immune system by inducing ferroptosis in tumor-associated neutrophils, potentially promoting tumor progression. Therefore, it is essential to explore GPX4-independent ferroptosis mechanisms specifically targeting tumor cells. Here, we demonstrate that the FDA-approved antidiabetic drug metformin potently enhances ferroptosis induced by ultrasmall manganese ferrite (MnFe₂O₄, MFO) nanoparticles in prostate cancer. Mechanistically, this combined effect operates independently of GPX4 suppression and hinges on metformin-mediated upregulation of transferrin receptor 1 (TfR1), which regulates iron homeostasis and elevates intracellular Fe²⁺ levels. Additionally, metformin promotes lipid peroxidation by upregulating acyl-CoA synthetase long-chain family member 4 (ACSL4). Notably, the combinational effect occurs only when prostate cancer cells first engulf sufficient MFO before metformin administration; simultaneous administration inhibits MFO uptake. To improve tumor-specific delivery, prostate-specific membrane antigen (PSMA) antibody-modified microbubbles assisted by ultrasound irradiation were used to facilitate precise intratumor accumulation of MFO in vivo. This therapeutic approach activates ferroptosis-mediated tumor suppression without GPX4 downregulation, underscoring the potential of sequential nanotherapy and metabolic regulation to synergistically overcome treatment resistance.
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