Lactylation in pulmonary fibrosis: current understanding and challenges

Pulmonary fibrosis (PF) is a progressive, chronic lung disease, which is accompanied by epithelial cell damage, fibroblast activation, and macrophage polarization; the fibrotic niche is primarily composed of these three cell types. The local microenvironment, composed of a fibrotic niche, participates in disease progression by altering epigenetic modifications. Lactylation is a novel post-translational modification involving the writing, removal, and recognition of lactyl groups. Studies have demonstrated that lactylation promotes profibrotic cellular phenotypes by altering the epigenetics. At the microenvironmental level, lactylation affects PF progression by influencing lung epithelial cells, fibroblasts, and macrophages in the fibrotic niche. Lactylation may promote the development of PF by affecting epithelial cell autophagy, cellular senescence, expression of proliferation or repair genes, apoptosis, ferroptosis, endoplasmic reticulum stress, and epithelial-mesenchymal transition and may influence the activation of fibroblasts and secretion of pro-fibrotic factors by macrophages. By focusing on the key cell types in the fibrotic microenvironment, in this review, we elaborate on the roles of lactic acid and lactylation in PF and the potential future research directions of lactylation in the field of PF. This review summarizes the potential pathways through which lactylation promotes PF, based on the current sites and roles of lactylation in epithelial cells, fibroblasts, and macrophages. In addition, by summarizing the current research methods of lactylation and their limitations, our review paves the way for future studies on lactylation and PF.