Keratin 18 functions as a lactyltransferase to trigger necroptosis in diabetic kidney disease by modulating Fas transcription.

Diabetic kidney disease (DKD) is a type of chronic renal injury induced by diabetes mellitus and is characterized by persistent proteinuria and progressive decreases in the glomerular filtration rate. Recent studies have highlighted the significance of histone lactylation and necroptosis in the pathogenesis of DKD. We explored the mechanisms by which lactate-induced histone H3 lysine-18 lactylation (H3K18la) and H3K27la promote necroptosis in DKD. Lactate-induced H3K18la and H3K27la modulated Fas transcription, contributing to necroptosis and DKD progression. Moreover, keratin 18 (KRT18), identified as a lactyltransferase, regulated H3K18la and H3K27la levels, subsequently inducing Fas transcription and necroptosis. Furthermore, ginsenoside Rc (gRc) inhibited KRT18 lactyltransferase activity by competing for the lactate binding site in KRT18. Notably, gRc treatment reduced the KRT18, H3K18la, H3K27la, and Fas levels and alleviated necroptosis and renal dysfunction in DKD models. In conclusion, KRT18 functions as a lactyltransferase to induce Fas transcription and necroptosis. Moreover, inhibiting KRT18-mediated histone lactylation via gRc is a potential strategy for treating DKD.