Shi Lili, Zhang Lin, Ma Zhenfang, Hu Zhaohui, Geng Zihan, Liu Hao, Wang Jingyuan, Feng Ke, Geng Yiheng, Liu Yan, Zhang Cunhui, Xie Yujia, Zou Mengqi, Liu Qingping, Yang Ze, Pang Yaxian, Niu Yujie, Bao Lei, Zhang Rong
Department of Occupational Health and Environmental Health, Hebei Medical University, Shijiazhuang, Hebei 050017, PR China.
Clinical Medical Research Center for Women and Children Diseases, Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan 250001, PR China.
J Hazard Mater. 2025 Sep 15;496:139286. doi: 10.1016/j.jhazmat.2025.139286. Epub 2025 Jul 17.
The widespread application of silica nanoparticles (SiNPs) presents potential health risks to humans, particularly leading to severe pulmonary fibrosis. Macrophage polarization is essential in SiNPs-induced pulmonary fibrosis. However, the underlying molecular mechanisms have not been fully elucidated. Recent studies have indicated that lactylation significantly influences macrophage polarization. In this study, we established an inflammatory-stage pulmonary fibrosis mouse model by intratracheal instillation of SiNPs over 28 days, revealing concurrent enhancement of macrophage M1 polarization and histone lactylation. In vitro experiments demonstrated that SiNPs drove RAW264.7 cells polarization to M1 type via H3K18 lactylation (H3K18la), accompanied by elevating IL-6 and TNF-α secretion. These cytokines were shown to upregulate the collagen I and α-SMA expression in NIH3T3 cells. Integrated CUT&Tag and RNA-seq analyses identified direct targeting of NOS2 gene-a key biomarker of macrophage M1 polarization by H3K18la. Notably, SiNPs downregulated SIRT3 expression, which enhanced H3K18la levels through dual mechanisms: delactylase activity and modulation of lactate metabolism. This SIRT3/H3K18la/NOS2 axis establishes a novel pathway driving macrophage M1 polarization in fibrotic microenvironments, positioning SIRT3 as a promising therapeutic target for intervening in SiNPs-induced pulmonary fibrosis.
二氧化硅纳米颗粒（SiNPs）的广泛应用给人类带来了潜在的健康风险，尤其是会导致严重的肺纤维化。巨噬细胞极化在SiNPs诱导的肺纤维化中至关重要。然而，其潜在的分子机制尚未完全阐明。最近的研究表明，乳酰化显著影响巨噬细胞极化。在本研究中，我们通过气管内滴注SiNPs 28天建立了炎症期肺纤维化小鼠模型，发现巨噬细胞M1极化和组蛋白乳酰化同时增强。体外实验表明，SiNPs通过H3K18乳酰化（H3K18la）驱动RAW264.7细胞极化为M1型，同时伴随着IL-6和TNF-α分泌增加。这些细胞因子被证明可上调NIH3T3细胞中I型胶原蛋白和α-SMA的表达。综合CUT&Tag和RNA-seq分析确定了H3K18la直接靶向巨噬细胞M1极化的关键生物标志物NOS2基因。值得注意的是，SiNPs下调了SIRT3的表达，SIRT3通过双机制增强了H3K18la水平：去乳酰化酶活性和乳酸代谢调节。这个SIRT3/H3K18la/NOS2轴建立了一条在纤维化微环境中驱动巨噬细胞M1极化的新途径，将SIRT3定位为干预SiNPs诱导的肺纤维化的一个有前景的治疗靶点。
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