Construction of an eight-disulfidptosis-related long non-coding RNA prognostic signature and mechanistic investigation of key molecule MKLN1-AS driving hepatocellular carcinoma progression via the miR-139-5p/LRPPRC axis.

backgroundHepatocellular carcinoma (HCC) poses a significant global health burden, with limited reliable prognostic biomarkers and effective therapeutic options. Disulfidptosis, a newly identified form of regulated cell death driven by disulfide stress, has emerged as a crucial player in tumor progression. However, the prognostic potential and biological functions of disulfidptosis-related long non-coding RNAs (DRLs) in HCC remain largely unexplored.

methodsUtilizing RNA-seq and clinical data from The Cancer Genome Atlas (TCGA)-LIHC cohort, we identified prognosis-related DRLs through Pearson correlation analysis. A prognostic signature was constructed via LASSO and multivariate Cox regression analyses. The model's performance was rigorously validated using Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. The tumor immune microenvironment and tumor mutational burden (TMB) were investigated to assess the model's immunotherapeutic relevance. ROC and survival analyses was used to identify the most prognostically significant lncRNA. Its expression was verified by quantitative real-time PCR (qRT-PCR) in 10 paired HCC and adjacent normal tissues, and its functional roles were validated through in vitro and in vivo experiments. Mechanistic investigation, including correlation analyses, miRNA target prediction (miRDB and DIANA), and dual-luciferase reporter assays, revealed its regulatory axis.

resultsWe established a novel prognostic signature based on eight DRLs, which effectively stratified HCC patients into high- and low-risk groups with distinct overall survival outcomes. Additionally, the high-risk group was characterized by an immunosuppressive microenvironment and higher TMB. MKLN1-AS showed the highest AUC value, with expression levels significantly upregulated in HCC tissues and correlated with disease progression, as indicated by increasing T stage and clinical grade. MKLN1-AS promoted HCC cell malignancy in vitro and in vivo. Mechanistically, MKLN1-AS acted as a competing endogenous RNA (ceRNA) to sponge miR-139-5p, thereby relieving its targeted inhibition of LRPPRC (a disulfidptosis-inhibiting gene), ultimately suppressing disulfidptosis and promoting HCC progression.

conclusionsOur study develops and validates a robust DRLs-based prognostic model for HCC, offering a valuable tool for risk stratification and outcome prediction. MKLN1-AS was identified as a novel oncogenic lncRNA that drives HCC progression via the miR-139-5p/LRPPRC axis to inhibit disulfidptosis. The functional and mechanistic elucidation of MKLN1-AS underscores its clinical relevance and highlights its potential as a promising therapeutic target for HCC.