Elucidating the role of AC026412.3 in hepatocellular carcinoma: a prognostic disulfidptosis-related LncRNAs model perspective.

[UNLABELLED] Disulfidptosis—a newly characterised mode of regulated cell death implicated in tumorigenesis—exhibits undefined prognostic utility in hepatocellular carcinoma (HCC), particularly concerning disulfidptosis-related long non-coding RNAs (DRLs). Integrating transcriptomic and clinical data from The Cancer Genome Atlas, we identified 807 DRLs and constructed a prognostic signature via univariate Cox regression, LASSO-Cox penalisation, and multivariate Cox analysis. The resulting four-DRL signature (,,,) stratified patients into distinct risk cohorts, with high-risk groups demonstrating significantly reduced overall survival (OS; log-rank  < 0.001) and hazard ratios independent of conventional clinicopathological variables. Model discrimination was robust across multiple metrics: time-dependent receiver operating characteristic curves yielded AUCs of 0.750 (95% CI: 0.676–0.817) at 1 year, 0.709 (0.637–0.781) at 3 years, and 0.720 (0.641–0.799) at 5 years, outperforming established staging systems. Concordance indices (C-index: 0.681) and principal component analysis further validated stratification efficacy. Functional annotation linked the signature to extracellular matrix dysregulation, epithelial-mesenchymal transition, and immunosuppressive microenvironments. High-risk patients exhibited elevated tumour mutational burden ( = 0.04), increased M0 macrophage infiltration, and heightened tumour immune dysfunction and exclusion (TIDE) scores ( < 0.001)—indicating impaired immunotherapy response. Pharmacogenomic profiling revealed enhanced sensitivity to five agents in high-risk subgroups (BDP-00009066, GDC0810, Osimertinib, Paclitaxel, YK-4-279; all  < 0.01). Critical experimental validation confirmed as an oncogenic driver: significantly overexpressed in HCC tissues ( < 0.001) and cell lines, its knockdown suppressed proliferation, invasion, and migration in vitro. In vivo models demonstrated its necessity for angiogenesis (chorioallantoic membrane assay), primary tumour growth (orthotopic implantation), pulmonary metastasis, and epithelial-mesenchymal transition activation. This molecularly annotated signature enables precise prognostic stratification and guides personalised therapeutic strategies in HCC.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12876-025-04174-6.