H3K18 lactylation promotes the progression of arsenite-related idiopathic pulmonary fibrosis via YTHDF1/m6A/NREP.

As epigenetic modifications, lactylation and N6-methyladenosine (m6A) have attracted wide attention. Arsenite is an environmental pollutant that has been proven to induce idiopathic pulmonary fibrosis (IPF). However, the molecular mechanisms of lactylation and m6A methylation are unclear in arsenite-related IPF (As-IPF). In view of the limited understanding of molecular mechanism of m6A and lactylation in As-IPF, MeRIP-seq, RNA-seq and ChIP-seq were analyzed to verify the target gene regulated by m6A and H3K18 lactylation (H3K18la). We found that, for As-IPF, the global levels of m6A, levels of YTHDF1 and m6A-modified neuronal protein 3.1 (NREP) were elevated in alveolar epithelial cells (AECs). The secretion levels of TGF-β1 were increased via YTHDF1/m6A/NREP, which promoted the fibroblast-to-myofibroblast transition (FMT). Further, extracellular lactate from myofibroblasts elevated levels of the global lactylation (Kla) and H3K18la via the lactate monocarboxylate transporter 1 (MCT1), and, in AECs, H3K18la facilitated the transcription of Ythdf1. This report highlights the role of crosstalk between AECs and myofibroblasts via lactylation and m6A and the significance of H3K18la regulation of YTHDF1 in the progression of As-IPF, which may be useful for finding effective therapeutic targets.