SLC7A11-mediated dual regulation of disulfidptosis and ferroptosis in silver nanoparticles-induced neurotoxicity in hippocampal neurons.

Authors

Shuyan Niu, Yu Ma, Haitao Yang, Menghao Guo, Chenyu Liu, Mengjing Cui, Tianshu Wu, Yuying Xue

Published in

Free radical biology & medicine. Aug 25, 2026. Epub Aug 25, 2026.

Abstract

Silver nanoparticles (AgNPs) are widely used for their antimicrobial properties in consumer and biomedical products, prompting concern about their potential neurotoxicity. However, the mechanisms by which AgNPs drive neuronal death across different exposure durations remain poorly defined. In this study we investigated the temporal dynamics and mechanisms by which AgNPs induce neurotoxicity in hippocampal neurons, focusing on the cystine-glutamate antiporter solute carrier family 7 member 11 (SLC7A11). Using combined in vivo (1-day acute and 28-day subacute intranasal exposure in mice) and in vitro (HT22 hippocampal neurons) models, together with inhibitors (deferoxamine, ferrostatin-1, TCEP), SLC7A11 siRNA, and surface-enhanced Raman spectroscopy (SERS) spectroscopy, we delineated a time-dependent switch between disulfidptosis and ferroptosis. Early (24 h) AgNPs exposure produced SLC7A11 up-regulation, cystine accumulation, NADPH depletion, GLUT1 down-regulation and F-actin collapse-features of disulfidptosis that were rescued by TCEP or SLC7A11 knockdown. With prolonged/subacute exposure, SLC7A11 and glutathione peroxidase 4 (GPX4) expression fell, iron homeostasis was disrupted, mitochondria showed ferroptotic morphology, hippocampal silver accumulated, and mice exhibited spatial memory deficits. SERS of AgNPs-cystine mixtures revealed cleavage of cystine disulfide bonds and formation of Ag-S complexes, a chemical transition that likely attenuates disulfide stress and facilitates the shift toward iron-dependent ferroptosis. Collectively, these data position SLC7A11 as a context-dependent metabolic switch governing the balance between disulfidptosis and ferroptosis, and provide a mechanistic basis to refine their safe and targeted application, particularly in biomedical contexts.

PMID:
42641966
Bibliographic data and abstract were imported from PubMed on 26 Aug 2026.

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