Long-term exposure to silica nanoparticles induces DNA damage by activating ferritinophagy in the lungs

Amorphous silica nanoparticles (SiNPs) have been extensively produced and applied; therefore, their adverse health effects after long-term exposure should be investigated thoroughly. This study demonstrated that long-term exposure to SiNPs led to persistent DNA damage in the lungs of rats. After treating BEAS-2B cells with SiNPs for 40 passages, γ-H2AX levels increased markedly, accompanied by enhanced cell migration and invasion. Activation of ferritinophagy and inhibition of H2A-ubiquitination-mediated DNA damage repair were observed both in vivo and in vitro. Further mechanistic studies indicated that SiNPs induced ferritinophagy activation, resulting in the accumulation of ferrous ions, which induced the cytoplasmic translocation of HERC2. The decreased HERC2 level in the nucleus inhibited H2A-ubiquitination-mediated DNA damage repair, leading to DNA damage. The ferritinophagy inhibitor chloroquine and ferrous ion chelator deferoxamine hindered the cytoplasmic translocation of HERC2, reversed the inhibition of DNA damage repair, and alleviated DNA damage. Furthermore, NCOA4-knockout alleviated DNA damage and the propensity for malignant cell transformation induced by long-term exposure to SiNPs. Notably, suppressing ferritinophagy may hold therapeutic potential for managing SiNPs-induced genotoxicity.