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.

石墨烯量子点 (GQD) 是一种极好的治疗诊断工具，广泛用于纳米医学应用。GQD 的生物安全性受到了广泛关注，但其潜在的毒理学机制仍未得到充分了解。为了研究石墨烯介导的变化背后的细胞和分子机制，整合了定量蛋白质组学和非靶向脂质组学。我们发现谷胱甘肽过氧化物酶 4 作为铁死亡的关键调节因子，在蛋白质水平上被 GQD 下调。在 GQD 处理的 RAW264.7 巨噬细胞中鉴定出具有铁死亡特征的脂质组学分析。此外，GQDs 暴露与 GSH 水平降低和脂质过氧化增加有关。GPX4 在 RAW264 中的过表达。7 细胞和 ferroptosis 抑制剂 Ferrostatin-1 (Fer-1) 的预处理不仅抑制了细胞死亡，而且减轻了脂质过氧化。总之，我们的结果表明，GQDs 暴露诱导 RAW264.7 巨噬细胞的铁死亡，并为 GQDs 的生物安全性评估提供了必要的数据。