Work

Metal–Organic Framework MIL-101 Induces Macrophage Ferroptosis through Depriving Cystine Uptake and Overloading Labile Iron Pool

Year: 2026

Type: article

Abstract: The wide applications of metal–organic frameworks (MOFs) in environmental remediation and biomedicine inevitably lead to their entry into the environment and human body, exerting unexpected risks. Recent studies have primarily focused on the cytotoxicity testing of MOFs; however, the toxicological mechanism has not been fully investigated. In this study, the cytotoxicity of representative Fe-based MOFs (i.e., MIL-53, MIL-88A, MIL-100, and MIL-101) was first screened, and only MIL-101 exerted cytotoxicity to macrophages. Mechanistically, MIL-101 was internalized by macrophages via the caveolin-mediated and macropinocytosis pathways, with subsequent location in lysosomes, inducing significant oxidative stress and mitochondrial dysfunction. Transcriptomic analysis revealed that ferroptosis was the primary mechanism underlying observed cytotoxicity. Specifically, MIL-101 led to the depletion of cystine by inhibiting the cystine transporter, thereby reducing the level of expression of glutathione peroxidase. Furthermore, the release of free Fe2+ from lysosomes and mitochondria, coupled with the decrease of the Fe2+-sequestering protein ferritin, destabilized the labile iron pool. Therefore, the decrease of glutathione and increase of free Fe2+ not only activated lipid peroxidation but also mobilized Fe2+ for Fenton reactions, ultimately resulting in ferroptosis. This study demonstrates that exposure to MIL-101 induces ferroptosis, which provides valuable insights into the rational design and sustainable use of MOF nanomaterials.

Source: Environment & Health

DOI: 10.1021/envhealth.6c00366