Yttrium oxide nanoparticles (Y 2 O 3 NPs), extensively utilized rare earth nanoparticles, exhibited a diverse range of applications across various fields, which leading to increased human exposure. Moreover, potential neurotoxic risks have been associated with their use, yet the underlying mechanism remains unclear. The present study aimed to investigate the effects of Y 2 O 3 NPs on cognitive function in rats with a particular focus on elucidating the pivotal role played by astrocytes in this process. The results demonstrated that Y 2 O 3 NPs induced cognitive and memory impairment in rats, copper (Cu) accumulation and cuproptosis of astrocytes as contributing factors. Furthermore, we elucidated that Y 2 O 3 NPs induced astrocytes cuproptosis by inhibiting TRIM24/DTNBP1/ATP7A signaling pathway-mediated cellular Cu efflux. We provide, for the first time, the important involvement of astrocytes in Y 2 O 3 NPs-induced neurotoxicity, elucidating that cuproptosis as the primary mode of cell death. These results offer valuable insights for the future safe application of rare earth nanoparticles in field of neurology.
Objective/BackgroundProstate cancer is the most commonly diagnosed malignancy in men worldwide, with high mortality rates and frequent metastasis at initial diagnosis, underscoring the need to elucidate its molecular mechanisms. TRIM2, an E3 ubiquitin ligase, plays critical roles in several cancers, but its function in prostate cancer remains unclear. This study aimed to investigate the expression, biological function, and clinical significance of TRIM2 in PCa progression.MethodsTRIM2 expression was analyzed using TCGA, GTEx, and GEO datasets, and validated in PCa and BPH tissues via qRT-PCR, western blot, and immunohistochemistry. Functional assays (CCK-8, wound healing, Transwell, flow cytometry) were performed in DU145 and PC-3 cells with TRIM2 overexpression or knockdown, and xenograft models assessed tumorigenicity in vivo. Proteomic sequencing combined with database prediction (UbiBrowser, BioGRID) identified DTNBP1 as a downstream substrate, confirmed by co-immunoprecipitation, ubiquitination assays, and cycloheximide chase. Drug sensitivity was evaluated using the GDSC database and molecular docking.ResultsTRIM2 was significantly downregulated in PCa tissues, with the lowest levels observed in advanced and castration-resistant cases, and its reduced expression independently predicted worse progression-free interval. ROC analysis demonstrated that TRIM2 effectively discriminated localized from advanced/CRPC disease. TRIM2 overexpression significantly suppressed malignant behaviors in vivo and vitro. Mechanistically, TRIM2 directly interacted with DTNBP1 and promoted its ubiquitin-proteasome-mediated degradation. Drug sensitivity analysis and molecular docking revealed that TRIM2 expression serves as a predictor of PCa cell sensitivity to clinically relevant agents, including olaparib and navitoclax.ConclusionOur findings establish the TRIM2-DTNBP1 axis as a key driver of PCa progression and position TRIM2 as a promising prognostic biomarker and a potential predictive indicator for guiding molecularly targeted therapies in advanced PCa.
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