Increased lipid peroxidation by graphene quantum dots induces ferroptosis in macrophages.

Graphene quantum dots (GQDs) are an excellent tool for theranostics, and are widely used in nanomedical applications. The biosafety of GQDs has received abundant attention, but their latent toxicological mechanisms remain inadequately understood. To investigate the cellular and molecular mechanisms underlying graphene-mediated changes, quantitative proteomics and untargeted lipidomics were integrated. We discovered that glutathione peroxidase 4 as a key regulator of ferroptosis, was down-regulated at the protein level by GQDs. Lipidomics profiling with features of ferroptosis was identified in GQDs-treated RAW264.7 macrophages. Furthermore, GQDs exposure was associated with reduced levels of GSH and increased lipid peroxidation. Overexpression of GPX4 in RAW264.7 cells and pre-treatment of a ferroptosis inhibitor Ferrostatin-1 (Fer-1) not only suppressed cell death, but also alleviated lipid peroxidation. Taken together, our results indicated that GQDs exposure induced ferroptosis in RAW264.7 macrophages, and provided essential data for biosafety evaluations of GQDs.