Long-term SiNPs exposure induced genetic instability and malignant transformation via SQSTM1/p62-mediated autophagy dysfunction in lungs

As one of the most widely used nanomaterials, silica nanoparticles (SiNPs) have raised significant concerns regarding their toxicity, while their potential carcinogenicity remains poorly understood. During occupational exposure, SiNPs primarily enter the human body through the respiratory tract, thus we aimed to investigate the SiNPs-induced malignant transformation and correlated mechanisms in lungs. Fischer 344 rats underwent weekly intratracheal instillation of SiNPs for six months, followed by an additional six-month observation period to evaluate long-term effects. Results demonstrated the development of precancerous lesions in lungs of rats, which were associated with increased pulmonary glucose metabolism, chronic inflammation, squamous metaplasia, and epithelial-mesenchymal transition (EMT). Similarly, BEAS-2B cells exposed to SiNPs over 40 passages exhibited enhanced abilities in proliferation, migration, invasion, and anchorage-independent colony formation. In addition, genotoxicity was observed in BEAS-2B cells, including increased micronucleus formation, aberrant cell division, and elevated chromosomal aberration frequency. Mechanistically, SiNPs activated SQSTM1/p62-mediated autophagy dysfunction, which in turn induced mitotic catastrophe by interfering with the MDM2/p53/Aurora B signaling pathway. Concurrently, SQSTM1/p62 accumulation suppressed DNA damage repair by enhancing its interaction with RNF168. Molecular docking simulation further predicted that SiNPs directly bind to SQSTM1/p62 through electrostatic interactions, inducing conformational changes in SQSTM1/p62. Notably, SQSTM1/p62-knockout significantly attenuated SiNPs-induced DNA damage and malignant transformation , and modulated the expression of Aurora B and RNF168 signaling pathways. These findings demonstrated the critical role of SQSTM1/p62-mediated autophagy dysfunction in SiNPs-induced genotoxicity and malignant transformation in lungs, offering novel insights into SiNPs-related carcinogenicity.