Comprehensive analysis of disulfidptosis-related genes identifies clinically actionable prognostic biomarkers in cholangiocarcinoma

Cholangiocarcinoma (CCA), a malignancy of the hepatobiliary system, lacks predictive biomarkers due to the scarcity of publicly available datasets. Disulfidptosis, a recently identified form of regulated cell death, is triggered by disulfide accumulation in SLC7A11-high tumor cells under glucose deprivation. Its role in CCA, however, remains unexplored. We systematically evaluated the transcriptional and mutational profiles of disulfidptosis-regulating genes (DRGs) in CCA. Based on their expression, distinct disulfidptosis clusters (CDR clusters) were defined. Differentially expressed genes (DEGs) derived from these clusters were used to classify the samples into Gene Cluster A and Gene Cluster B. A subsequent prognostic risk model was then developed. Clinical characteristics, immune cell infiltration (assessed via Immune Score and ESTIMATE Score), and drug sensitivities were compared between high- and low-risk groups. Most disulfidptosis-regulating genes exhibited significant differential expression and prognostic value in CCA. DEG analysis defined Gene Clusters A/B. Four key genes—RTN4RL1, SLC13A1, FOSL1, and COX6B2—were identified to construct the prognostic model. The high-risk group exhibited significantly poorer overall survival in both the training cohort (n = 262; AUC 1–3 years: 0.796–0.819) and an independent external validation cohort (n = 30; AUC 1–3 years: 0.804–0.868). Multivariate analysis confirmed the risk score as an independent prognostic factor. The high-risk group demonstrated significantly elevated Immune Scores and ESTIMATE Scores. Drug sensitivity analysis revealed differential responses between risk groups, identifying potential therapeutic agents for CCA. qPCR validation in independent CCA patient specimens confirmed significant upregulation of high-risk genes (FOSL1, COX6B2) and downregulation of low-risk genes (RTN4RL1, SLC13A1) in tumor tissues, corroborating our bioinformatic findings. This represents the first systematic exploration of the prognostic associations and tumor microenvironment implications of disulfidptosis-related genes (DRGs) in CCA. Our findings elucidate the role of disulfidptosis, reveal its association with the tumor immune microenvironment, and our in silico drug sensitivity analysis generates hypotheses for potential therapeutic strategies that may be tested in future preclinical studies.