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

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.