Lactate-fueled H3K18 lactylation sustains ΔNp63α-dependent self-renewal in limbal epithelial stem cells

The interplay between metabolic reprogramming and epigenetic regulation in controlling stem cell fate remains incompletely understood, particularly in limbal epithelial stem cells (LESCs) that are essential for corneal homeostasis. Here, we identify glycolytic lactate as a critical metabolic regulator that sustains LESC self-renewal through an epigenetic mechanism. We established a progenitor-like LESC model via MYC overexpression (oeMYC-LESCs). Using CUT&Tag, RNA-seq, and a mouse corneal epithelial injury model, we found that oeMYC-LESCs exhibit enhanced glycolysis and lactate efflux, which fueled p300/CBP-mediated histone lactylation, especially histone H3 lysine 18 lactylation (H3K18la). Enrichment of H3K18la at the ΔNp63α promoter drives its transcriptional activation, thereby sustaining LESC self-renewal. Inhibition of lactate generation depleted H3K18la, suppressed ΔNp63α, and consequently impaired LESC function; notably, these phenotypes were partially rescued by exogenous lactate supplementation. In vivo experiments confirmed that lactate accelerates corneal re-epithelialization and upregulates ΔNp63α in an H3K18la-dependent manner, whereas pharmacological blockade of lactate production delayed wound healing. Collectively, our study reveals a lactate-H3K18la-ΔNp63α axis as a key metabolic-epigenetic-transcriptional mechanism sustaining LESC self-renewal, suggesting a novel therapeutic target for treating limbal stem cell deficiency.