H3K18 lactylation drives the progression of silica nanoparticles-induced pulmonary fibrosis via promoting macrophage M1 polarization

Abstract

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.

Keywords: Histone lactylation; Macrophage polarization; Pulmonary fibrosis; Silica nanoparticles.