Lactylation-related Gene DDX21 Modulates Immune Regulation and Serves As a Pivotal Biomarker for Breast Cancer

Background: Lactylation is a novel form of post-translational modification. The role of lactylation in breast cancer (BRCA), especially its interplay with immune response and metabolism, remains to be explored. This study utilized bioinformatics analysis to identify genes related to lactate production and preliminarily explored their roles in BRCA. Methods: Using data from The Cancer Genome Atlas database (TCGA) and dataset GSE20685, we analyzed the expression and mutation patterns of lactylation-related genes (LRGs). Unsupervised clustering was performed to screen lactylation-related clusters. We further investigated the presence, functional location, and association with BRCA of global lactylation. Following Cox regression and LASSO regression analyses, a LRG model was developed and validated. Subsequently, the associations of LRGs-based risk model with clinical features, immunotherapy responses, immune cell infiltration, mutation landscape, and biological functions were explored. Single-cell expression levels of core genes were also determined. Finally, the functional role of the core gene was validated through in vitro assays (MTT, colony formation, Transwell) and in vivo xenograft models. Results: An elevation of global lactylation was observed, particularly in malignant tumors such as BRCA. Thereafter, a 4-LRG risk model was developed for predicting the prognosis of BRCA. High-and low-risk BRCA groups exhibited significant differences in biological functions, checkpoint expressions, immune cell infiltrations, immunotherapy responses, drug sensitivities, and clinical features. Further analysis revealed that DDX21 was widely expressed in various cell types of BRCA, indicating a potential role in immunity regulation in BRCA. In addition, silencing DDX21 can inhibit the growth of BRCA cells in vitro and xenograft tumor growth in vivo. Conclusions: We developed a lactylation-related prognostic model and identified DDX21 as a key oncogenic driver and potential therapeutic target in BRCA. However, the lack of clinical research on DDX21 is the main limitation of this study.