Abstract

Background Lactylation, a protein modification driven by lactate produced during glycolysis, has been implicated in tumorigenesis and immune suppression, and may influence patient prognosis. This study aimed to identify lactylation-related prognostic genes and explore their potential functional relevance. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify lactylation-related genes (LRGs) in esophageal cancer (ESCA). Prognostic LRGs were determined by univariate and multivariate Cox regression analyses. Correlations of prognostic LRGs with ESCA-associated genes, immune cell infiltration, and five classes of immunomodulatory genes were evaluated, followed by functional enrichment and drug sensitivity analyses. These LRGs were validated using an independent dataset and immunohistochemistry (IHC) assays. Results A total of 321 predictive LRGs were identified in ESCA. Four LRGs ( GADD45B , HMGB3 , LMNB2 , and MFAP5 ) were further recognized as independent prognostic factors (P<0.05). These genes were significantly associated with ESCA-related genes, tumorigenesis, and immune-inflammatory processes. Moreover, they showed significant correlations with immune cells (e.g., activated B cells, natural killer T cells) and multiple immunomodulatory genes (such as CSF1R , CXCL12 , CCL23 , and CCR2 ). In addition, the four LRGs had different sensitivities to the drugs 5-fluorouracil, gefitinib, paclitaxel, sorafenib, vincristine, and cisplatin. HMGB3 knockdown significantly inhibited the viability, migration, and invasion of KYSE-140 cells while promoting cell apoptosis. Conclusions We identified four genes associated with lactylation activity scores that serve as independent prognostic candidates for ESCA. These LRGs hold promise as potential therapeutic targets and prognostic biomarkers in ESCA.