Work

Histone Lactylation Drives WNK1 Expression to Promote Esophageal Squamous Cell Carcinoma Progression Through Histone H3 Ser10 Phosphorylation

Year: 2026

Type: article

Abstract: Esophageal squamous cell carcinoma (ESCC) lacks effective targeted therapies, and how metabolic reprogramming drives oncogenic signaling remains poorly defined. Here, we identify histone H3 lysine 23 lactylation (H3K23la) as a key epigenetic mediator linking lactate accumulation to tumor progression. H3K23la is upregulated in ESCC and correlates with poor prognosis. Mechanistically, H3K23la promotes WNK lysine deficient protein kinase 1 (WNK1) transcription, which increases histone H3 Ser10 phosphorylation (p-H3S10) and enhances AKT transcription, thereby driving PI3K-AKT signaling. This defines a lactate-H3K23la-WNK1-p-H3S10-AKT axis connecting metabolism to oncogenic signaling. Importantly, pharmacological inhibition of WNK1 by CD03017 disrupts this pathway and suppresses tumor growth in vitro and in patient-derived xenograft (PDX) models. In conclusion, our findings define a metabolic-epigenetic-signaling axis in ESCC and establish WNK1 as a potential therapeutic target downstream of histone lactylation.

Source: Advanced Science

DOI: 10.1002/advs.78438