Significant contribution of autophagy in mitigating cytotoxicity of gadolinium ions

Gadolinium-based contrast agents (GBCAs) are widely used in clinical magnetic resonance imaging (MRI). Free gadolinium ions (Gd³⁺) released from GBCAs potentially increase the risk of GBCA-related toxicity. However, the cellular responses to Gd³⁺ and the underlying mechanisms responsible for protection against Gd³⁺ remain poorly understood. Recently, autophagy has been considered a cell survival mechanism against various toxic metals. Here, we investigated the relationship between Gd³⁺ and autophagy, as well as the effect of autophagy inhibition on the survival of cells exposed to Gd³⁺. We found that the increased expression of microtubule-associated protein 1 light chain 3 (LC3)-II, a marker protein of autophagy, in Gd³⁺-exposed human embryonic kidney 293 (HEK293) cells. Moreover, we found a greater accumulation of LC3-II after exposure to an autophagy inhibitor, chloroquine (CQ), combined with Gd³⁺ than that after exposure to CQ alone, suggesting that Gd³⁺ activated autophagy in HEK293 cells. Furthermore, we found that Gd³⁺ reduced cell viability, which was more pronounced after CQ treatment. Our findings indicated that autophagy exerted a cytoprotective effect against Gd³⁺ toxicity, suggesting a potential link between autophagy and GBCA-associated adverse events.