Abstract
BACKGROUND: Disulfidptosis is a newly discovered programmed cell death pathway that may be connected to tumorigenesis and development, showing promise as a novel treatment strategy for cancer. This study aims to construct a prognostic model of disulfidptosis-related Long non-coding RNAs (DRLRs) within the Asian HCC population and to investigate the impact of DRLRs on HCC. METHODS: Utilising a combination of univariate Cox, Lasso-Cox, and multivariate Cox analyses, five pivotal DRLRs (AC099850.3, ZNF337-AS1, LINC01138, AL031985.3, AC131009.1) were identified, forming a robust prognostic signature. Subsequent validations included Receiver Operating Characteristic (ROC) and Concordance Index analyses, alongside Principal Component Analysis. Comprehensive bioinformatics analysis was performed on the hub DRLRs, followed by experimental validation using quantitative real-time polymerase chain reaction and cellular functional assays. RESULTS: The risk score independently predicted prognosis, outperforming traditional clinical-pathological factors across varying ages, tumour stages, and pathological classifications in the cohort. A nomogram integrating these variables demonstrated capability in forecasting survival. Multivariate analysis confirmed that the risk score and AJCC TNM staging are independent prognostic factors for predicting overall survival (OS) in Asian HCC patients (both P < 0.001). The prognostic model's ROC area under the ROC values for 1-, 3-, and 5-year predictions were 0.837, 0.794, and 0.783, respectively, indicating its strong diagnostic and prognostic value. Pathway and immune landscape analyses elucidated the biological underpinnings and immune modulations associated with the high-risk group. Immune landscape analysis indicated that both immunescore (P < 0.001) and estimatescore (P < 0.05) were significantly decreased in the high-risk group, with both specific and non-specific immune responses being significantly suppressed, while the tumour immune dysfunction and exclusion score was notably increased (P < 0.001). Tumour mutational burden (TMB) analysis revealed a significantly higher TMB in the high-risk group (P = 0.033) and shorter OS for HCC patients in the high TMB subgroup (P = 0.002). Notably, Potential chemotherapeutic agents (PFI3, 5-Fluorouracil, BPD-00008900, GDC0810, and AZ6102) were identified for high-risk group. Experimental validations through quantitative PCR and in vitro assays confirmed the deregulation of these DRLRs in HCC, with functional studies highlighting the potential of ZNF337-AS1 silencing in curtailing tumour invasiveness. CONCLUSION: Our investigations validate a DRLR-based risk scoring model as an effective prognostic tool for Asian HCC. This model not only enhances understanding of disulfidptosis's role in HCC but also facilitates personalised treatment strategies, potentially improving patient outcomes.