Lactate Promotes Collagen Expression, Proliferation, and Migration through H3K18 Lactylation-Dependent Stimulation of...

Keloids are fibroproliferative dermal lesions characterized by unrestrained fibroblast proliferation, collagen overproduction, and persistent enlargement. Lactate has been suggested to regulate keloid fibroblast activity, although the underlying mechanism remains unclear. Histone lactylation is an important epigenetic regulatory mechanism through which lactate regulates pathophysiological processes, but its role in keloids remains to be studied. In this study, we discovered that the levels of pan-lysine lactylation and H3K18 lactylation were markedly increased in keloid fibroblasts and that H3K18 lactylation mediated the positive effects of lactate on keloid fibroblast collagen expression, proliferation, and migration. Furthermore, we found that lactate stimulated TGF-β1 secretion through H3K18 lactylation-dependent upregulation of LTBP3 transcription; in turn, TGF-β1 increased the lactate and H3K18 lactylation levels, possibly forming a positive feedback loop to continuously promote fibroblast collagen expression, proliferation, and migration. Our data revealed that H3K18 lactylation plays a key role in keloid fibroblasts, elucidated the pathomechanisms underlying keloids, and identified potential treatment targets.