BAY-876

Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising strategy for antitumor immunotherapy. However, its therapeutic efficacy is hindered by the persistently high intracellular glutathione (GSH) level driven by metabolic compensation. Herein, we report a ferroptosis-inducible polymeric nanovesicle encapsulated with BAY-876 and ferrous ion (Fe²⁺) (FIPNV/B@Fe²⁺) to potentiate ferroptosis-immunotherapy via perturbing metabolic compensation. Mechanically, double bonds in the polymeric side chain deplete the intracellular GSH and coordinated Fe²⁺ facilitates lipid peroxidation, a process concomitant with GSH consumption. BAY-876 abrogates glucose utilization and suppresses the production of adenosine triphosphate (ATP), prostaglandin D2 (PGD₂) and lactate. Consequently, GSH biosynthesis is inhibited through energy depletion and NADPH competition, thereby amplifying ferroptosis. Additionally, reduced extracellular lactate coupled with elevated glucose in the tumor microenvironment (TME) remodels the immunosuppressive TME by modulating tumor-associated macrophage polarization and T lymphocyte proliferation. In vivo studies validate that FIPNV/B@Fe²⁺ effectively suppresses 4 T1 tumor growth, recurrence, and rechallenge progression. Upon combination with the immune checkpoint inhibitor, this strategy further inhibits lung metastasis in both 4 T1 and B16F10 models. Overall, this study highlights the regulatory role of ATP and PGD₂ in boosting ferroptosis and establishes a smart nanoplatform for synergistic regulation of ferroptosis-immunotherapy through metabolic compensation perturbation.

Lead (Pb) is a neurotoxic environmental pollutant that causes cognitive dysfunction and metabolic disturbances in the brain. Glucose transporter 1 (GLUT1) is essential for cerebral glucose metabolism, and altered expression may impair glucose uptake and utilization, synaptic plasticity, and cognitive performance. We found that acute Pb exposure impaired learning, memory, and anxiety-related behavior of mice. Fasting blood glucose concentrations increased in Pb-exposed mice, whereas GLUT1 expression in the brain was significantly decreased. GLUT1 overexpression alleviated Pb-induced synaptic structural and functional damage in Neuro-2a cells, whereas GLUT1 knockdown exacerbated these effects. Co-treatment with Morinda officinalis oligosaccharides (MOOs) improved behavioral performance, restored GLUT1 expression, and reduced Pb-induced synaptic pathology, whereas BAY-876 aggravated neurological impairment. In conclusion, GLUT1 is a key regulator of Pb-induced neurotoxicity. These findings provide potential therapeutic strategies for preventing the neurotoxic effects of Pb.