Chen_2025_Front.Immunol_16_1604758

BACKGROUND: Lactate-driven metabolic reprogramming and histone lactylation play pivotal roles in bladder cancer (BLCA) progression, yet their underlying mechanisms and regulatory genes remain poorly understood. METHODS: Using transcriptomic data from The Cancer Genome Atlas (TCGA), we identified lactylation-associated genes and constructed a prognostic signature. Comprehensive bioinformatics analyses were conducted to assess immune infiltration, tumor microenvironment characteristics, and the lactylation landscape at the single-cell level. Furthermore, we performed in vitro experiments to evaluate the biological functions of key lactylation-related genes in BLCA cells. RESULTS: Six lactylation-related hub genes were identified, among which FASN and RUNX2 were significantly upregulated in BLCA and associated with poor prognosis. Single-cell analyses revealed elevated lactylation signatures in tumor epithelial and immune cells. Knockdown of FASN or RUNX2 in BLCA cell lines significantly suppressed cell proliferation, induced apoptosis, and reduced intracellular lactate levels. Correspondingly, global protein lactylation was diminished, with dominant modification signals observed around 40 kDa, indicating a potential set of non-histone proteins as key functional targets. CONCLUSIONS: Our study highlights a metabolic-enzymatic axis wherein FASN and RUNX2 regulate lactate-driven protein lactylation in BLCA. These findings provide new insights into the non-histone functions of lactylation and suggest potential therapeutic targets at the intersection of metabolism and tumor immunity.