Inhibition of H3K14 lactylation promotes diabetic corneal nerve regeneration via Wnt1/beta-catenin signaling

Ocul Surf. 2026 Feb 2;40:40-51. doi: 10.1016/j.jtos.2026.01.008. Online ahead of print.

ABSTRACT

AIMS: This study bridges diabetes-induced metabolic alterations and corneal neuropathy, proposing lactylation as a key mechanistic and therapeutic target in diabetic keratopathy (DK).

METHODS: We used a streptozotocin-induced Type 1 diabetes mellitus (T1DM) mouse model to examine metabolic reprogramming in trigeminal ganglion (TG) neurons and its effects on corneal nerve regeneration. Glycolysis, lactate levels, and histone lactylation (H3K14la) were analyzed via Western blot, qPCR, immunofluorescence, and enzymatic assays. Genome-wide H3K14la profiling was conducted using CUT&Tag, followed by KEGG pathway analysis. Functional studies involved AAV-mediated gene modulation to evaluate lactate and Wnt1/β-catenin signaling roles, with outcomes assessed by corneal sensitivity tests, epithelial wound healing assays, and β-tubulin III-based nerve density quantification.

RESULTS: T1DM mice exhibited enhanced glycolysis in TG neurons, elevated lactate levels, and increased H3K14la enrichment, particularly at the Wnt1 promoter. CUT&Tag revealed genome-wide upregulation of H3K14la peaks, with significant enrichment in the Wnt signaling pathway. Elevated H3K14la repressed Wnt1 transcription, leading to suppression of the Wnt1/β-catenin pathway and downregulation of regenerative targets cyclin D1 and c-myc. LDHA knockdown reduced lactate and H3K14la levels, restored Wnt1/β-catenin activity, and promoted corneal nerve regeneration and wound healing, whereas LDHA overexpression exacerbated deficits. Wnt1 overexpression rescued corneal nerve function in diabetic mice, while Wnt1 knockdown abolished the benefits of LDHA suppression.

CONCLUSIONS: Hyperglycemia-driven glycolysis increases lactate-mediated H3K14la at the Wnt1 promoter, repressing Wnt1/β-catenin signaling and impairing corneal nerve regeneration. Targeting lactate metabolism or histone lactylation represents a promising therapeutic strategy for DK.

PMID:41638550 | DOI:10.1016/j.jtos.2026.01.008