Ferroptosis Induced By Two Dimensional Nanosheets

Radiation and nanoparticles as two important environmental pollutants may induce acute or chronic damages in organs and threat human health.Their toxicity mechanism studies may facilitate the diagnosis and treatment of related diseases in clinics,and provide fundamental theories for environmental and health protections.Substantial studies indicated that radiation and nanoparticles induce toxic effects through apoptosis,necrosis and inflammatory responses,resulting in adverse outcomes to human beings.Lysosomal damage and reactive oxygen species release are two conventical cellular events in the toxicity pathways of nanoparticles and radiations.Recently,ferroptosis as a new cell death was found to strongly associate with lysosomal damages and reactive oxygen species generation.However,we know few of the relationships between ferroptosis and nanoparticle/radiation exposures.This study aimed to address this problem by examining the ferroptosis signals induced by radiation and nanoparticles,and made following findings:ⅰ)Establishment of detection methods for ferroptosis.At the cellular level,we used inducer(erastin)and inhibitor(Ferrostatin-1)to modulate ferroptosis and detect the ferroptotic biomarkers including the accumulation of iron,the production of reactive oxygen species and the accumulation of lipid peroxides by confocal fluorescence microscopy.A high-throughput cell activity detection method based on metabolic enzyme activity was established.ⅱ)The ferroptosis signals induced by X-ray,y ray and environmental nanoparticles were examined.It was found that X-ray and y ray at 0-12 Gy induced limited ferroptosis effects in pulmonary respiratory tract epithelial cell BEAS-2B;WS2,MoS2 and graphene oxide(GO)induced significant ferroptotic cell death.ⅲ)The ferroptosis mechanism induced by WS2,MoS2 and GO were elucidated.After internalization into lysosomes,WS2 and MoS2 induced lysosomal dysfunction,Fe2+ release into cytoplastic compartment.This may elicit lipid peroxidation by Fenton reactions along with the down-regulation of glutathione peroxidase 4(GPX4)that account for clearance of lipid peroxides.These hazard signals may eventually lead to ferroptosis.GO induced ferroptosis by disrupting the iron homeostasis.ⅳ)The biological structure-activity relationships(SARs)of ferroptosis induced by WS2 and MoS2 nanoplates have been explored.And the safe design has been developed.Firstly,a combinational library of 20 nanosheets was established to examine the correlations between five physicochemical properties and cell deaths.As a result,surface vacancies were found to dictate the ferroptosis effects induced by WS2 and MoS2 nanosheets.According to the identified nano-SARs,WS2 and MoS2 nanosheets were subjects to safe design by Na2S and methanol treatment for vacancy healing.This surface functionalization significantly ameliorated the cytotoxicity of WS2 and MoS2 with 30.0%and 20.8%increments of cell viability,52.1%and 47.8%reductions of cytokines in animal lungs,respectively.In summary,this study has explored the following conclusions:ⅰ)the radiation exposure at 0-12 Gy induced negligible ferroptotic effects;ⅱ)WS2,MoS2 and GO nanoplates enabled to induce significant ferroptosis;ⅲ)the surface vacancy of WS2 and MoS2 nanosheets was the key surface properties responsible for ferroptosis;iv)Na2S and methanol pretreatment could enhance the biosafety of WS2 and MoS2 nanosheets by healing surface vacancies.This study has following implications:ⅰ)discovery of WS2 and MoS2 induced ferroptosis provides new insights for exploration of ferroptosis inducers;ⅱ)elucidating a new ferroptosis mechanism featured by the disruption of subcellular Fe2+ distributions;ⅲ)the developed safe design approaches may facilitate the biomedical use of WS2 and MoS2 nanosheets.