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 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.
Li et al. (2026) studied this question.