Integrated analysis identifies disulfidptosis related tumor antigens and molecular subtypes in hepatocellular carcinoma for mRNA vaccine development

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies worldwide, yet its molecular heterogeneity continues to limit the efficacy of systemic therapies. Disulfidptosis, a recently characterized form of regulated cell death triggered by disulfide stress under glucose deprivation in SLC7A11-overexpressing cells, represents a promising but poorly characterized therapeutic target in HCC. Here, we established an integrated disulfidptosis-based framework encompassing molecular subtyping, mRNA vaccine design, and prognostic modeling. Transcriptomic data from TCGA-LIHC and GEO datasets were integrated after batch-effect correction. Thirty-two disulfidptosis-related genes (DRGs) defined two molecularly distinct HCC subtypes with significant differences in survival outcomes, immune cell infiltration, and pathway enrichment. Through mutation profiling and survival analysis, tumor-associated antigens WASF2 and LRPPRC were identified as optimal vaccine targets, both exhibiting high mutation frequencies, adverse prognostic associations, and positive correlation with antigen-presenting cell abundance. A multi-epitope mRNA vaccine incorporating B-cell, CTL, and HTL epitopes was computationally designed and validated for strong antigenicity, non-allergenicity, non-toxicity, and favorable physicochemical properties; in silico immunosimulation predicted robust humoral and cellular immune responses. Furthermore, a disulfidptosis-related lncRNA prognostic index (DRI) was constructed via LASSO-Cox regression, effectively stratifying patients by prognosis (AUC > 0.7) and predicted responsiveness to immune checkpoint inhibitors. This multi-dimensional framework linking disulfidptosis biology to HCC subtype classification, immunotherapy-oriented vaccine development, and patient stratification offers a compelling foundation for advancing precision immunotherapy in HCC.