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  3. H3K18 lactylation-mediated SIX1 upregulation contributes to silica-induced epithelial-mesenchymal transition in airway epithelial cells

H3K18 lactylation-mediated SIX1 upregulation contributes to silica-induced epithelial-mesenchymal transition in airway epithelial cells

  • Toxicology. 2025 Mar 4:514:154109. doi: 10.1016/j.tox.2025.154109.
Songtao Liu 1,  Yiting He 1,  Linling Jin 1,  Shuangshuang Shi 1,  Jiayi Zhang 1,  Weiping Xie 1,  Mingxia Yang 2,  Qun Zhang 3,  Hui Kong 4
Affiliations

Affiliations

  • 1 Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210000, China.
  • 2 Department of Pulmonary & Critical Care Medicine, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213003, China.
  • 3 Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210000, China. Electronic address: qunzhang_qz@163.com.
  • 4 Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210000, China. Electronic address: konghui@njmu.edu.cn.
PMID: 40049282 DOI: 10.1016/j.tox.2025.154109
Abstract

Silica exposure-induced airway epithelial-mesenchymal transition (EMT) is a critical pathological process in pulmonary fibrosis. This study investigated the role of NLRP3 inflammasome, glycolysis, and histone lactylation in silica-induced EMT of human bronchial epithelial cells (16HBE). Silica exposure activated NLRP3 inflammasome, enhanced glycolysis and H3K18 lactylation, as well as induced EMT in 16HBE cells. Selective inhibition of NLRP3 inflammasome with MCC950, blockade of the interleukin 1 (IL-1) receptor with AF12198, or suppression of lactate production with oxamate effectively reduced glycolysis-mediated histone lactylation and mitigated silica-induced EMT. Moreover, silica-induced upregulation of PFKFB3, a key Enzyme of glycolysis, was significantly mitigated by MCC950 or AF12198. Cut&Tag analysis revealed silica treatment led to H3K18 lactylation enrichment at transcription start sites (TSS), particularly within the promoter region of the sine oculis homeobox 1 (SIX1), which enhanced transcription of SIX1, a key transcription factor involved in EMT. Consistently, inhibition of histone lactylation by the Histone Acetyltransferase P300 inhibitor A-485 suppressed silica-induced SIX1 expression and EMT. These findings indicate that silica activates NLRP3 inflammasome and promotes interleukin 1β (IL-1β) production, thereafter enhancing PFKFB3-mediated glycolysis by IL-1 receptor. Lactate accumulation by glycolysis enhances H3K18 lactylation at the TSS facilitating expression of SIX1. Together, this inflammation-glycolysis-lactylation cascade involved in EMT provides new insights into the molecular mechanisms underlying silica-induced pulmonary fibrosis.

Keywords

Epithelial-mesenchymal transition (EMT); Glycolysis; Histone lactylation; NLRP3 inflammasome; SIX1; Silica.

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