Lactylation prognostic signature identifies DHCR7 as a modulator of chemoresistance and immunotherapy efficacy in bladder cancer

元桥 赵^*Zhuo Xing

• Second Xiangya Hospital, Central South University, Changsha, China

Background: Bladder cancer (BLCA), the 10th most common cancer worldwide, presents a worsening prognosis as the disease progresses. Reliable tools for predicting BLCA prognosis and treatment efficacy remain urgently needed. Methods: Expression profiles of lactylation related genes were analyzed utilizing the Cancer Genome Atlas (TCGA) database and BLCA data from the GSE13507 dataset. Two distinct clusters were identified through unsupervised clustering analysis. Lactylation associated gene signatures were established and subsequently validated using training cohort and different validation cohorts. Immune cell infiltration patterns and drug response profiles were systematically evaluated. Parallel analyses of lactylation related genes were conducted at the single-cell resolution. A series of in vivo and vivo experiments were subsequently performed to validate the findings. Results: We examined the mRNA expression profiles of 22 lactylation related genes in BLCA tissues. Through comprehensive analysis, we identified two distinct lactylation clusters that exhibited significantly different clinical outcomes and tumor immune microenvironment characteristics. Building upon these findings, we subsequently stratified patients into two molecular subtypes according to the lactylation clusters and established a robust genetic signature for predicting survival outcomes in BLCA patients.The lactylation risk score showed a strong connection with survival outcomes and correlated with the tumor microenvironment (TME) immunosignature and predicted immunotherapy efficacy. DHCR7 emerged as a pivotal prognostic gene from the nine gene model, prompting subsequent focused analyses. Single-cell analysis further confirmed that DHCR7 exhibits high expression in tumor epithelial cells and maintains a close association with various immune cells. For the first time, we identified that knockdown of DHCR7 enhances the efficacy of both cisplatin chemotherapy and immunotherapy, highlighting DHCR7 as a key player in cisplatin resistance and its influence on immunotherapy effectiveness in BLCA. These findings offer valuable insights into potential combined therapeutic strategies.We developed a robust lactylation risk prediction model for accurately forecasting BLCA prognosis and identified DHCR7 as a pivotal biomarker involved in cisplatin resistance and influencing immunotherapy efficacy in BLCA.