Yan Kanglin, Ma Yuexiao, Shi Xuemin, Liang Chen, Ding Ruiyang, Sun Zhiwei, Duan Junchao
Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China.
Beijing Key Laboratory of Environment and Aging, Capital Medical University, Beijing, 100069, PR China.
Mater Today Bio. 2025 Jun 9;33:101972. doi: 10.1016/j.mtbio.2025.101972. eCollection 2025 Aug.
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.
作为使用最广泛的纳米材料之一，二氧化硅纳米颗粒（SiNPs）已引发了对其毒性的重大关注，而其潜在的致癌性仍知之甚少。在职业暴露期间，SiNPs主要通过呼吸道进入人体，因此我们旨在研究SiNPs诱导的肺部恶性转化及其相关机制。Fischer 344大鼠每周经气管内滴注SiNPs，持续6个月，随后再进行6个月的观察期以评估长期影响。结果表明，大鼠肺部出现了癌前病变，这与肺葡萄糖代谢增加、慢性炎症、鳞状化生和上皮-间质转化（EMT）有关。同样，暴露于SiNPs超过40代的BEAS-2B细胞在增殖、迁移、侵袭和非锚定依赖性集落形成方面表现出增强的能力。此外，在BEAS-2B细胞中观察到了遗传毒性，包括微核形成增加、异常细胞分裂和染色体畸变频率升高。从机制上讲，SiNPs激活了SQSTM1/p62介导的自噬功能障碍，进而通过干扰MDM2/p53/极光激酶B信号通路诱导有丝分裂灾难。同时，SQSTM1/p62的积累通过增强其与RNF168的相互作用抑制了DNA损伤修复。分子对接模拟进一步预测，SiNPs通过静电相互作用直接与SQSTM1/p62结合，诱导SQSTM1/p62的构象变化。值得注意的是，敲除SQSTM1/p62可显著减轻SiNPs诱导的DNA损伤和恶性转化，并调节极光激酶B和RNF168信号通路的表达。这些发现证明了SQSTM1/p62介导的自噬功能障碍在SiNPs诱导的肺部遗传毒性和恶性转化中的关键作用，为SiNPs相关的致癌性提供了新的见解。
