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

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology Pub Date : 2025-03-04 DOI:10.1016/j.tox.2025.154109

Songtao Liu , Yiting He , Linling Jin , Shuangshuang Shi , Jiayi Zhang , Weiping Xie , Mingxia Yang , Qun Zhang , Hui Kong

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引用次数: 0

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.

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来源期刊

Toxicology 医学-毒理学

CiteScore

7.80

自引率

4.40%

发文量

222

审稿时长

23 days

期刊介绍： Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.