LncRNA regulation of pyroptosis determines prognostic outcomes and functional characteristics in liver cancer.

[UNLABELLED] Pyroptosis has been shown to play a dual role in the immune microenvironment and tumor progression of various cancers. Long noncoding RNAs (lncRNA) exert tumor suppressor or tumor promoter effects by regulating the expression of pyroptosis-related genes or the activity of signaling pathways. In this study, 30 differentially expressed genes related to pyroptosis were screened from 624 liver cancer patients’ RNA-seq datasets and 299 non-tumor adjacent tissue RNA-seq datasets, and 7 core genes were revealed to have significant co-expression relationships with multiple lncRNAs. Combined with lncRNA co-expression analysis and LASSO regression, three pyroptosis-related lncRNAs (pRLs) were finally identified (AC012615.1, AC099850.3 and AP001453.2) to construct a risk scoring model. Kaplan-Meier survival analysis showed that the overall survival time of patients in the low-risk group was significantly longer than that in the high-risk group ( < 0.001). ROC analysis showed that the model had a good predictive ability with a prediction AUC of 0.659, 0.657 and 0.751 for 1-year, 3-year and 5-year survival. Multivariate Cox regression confirmed that the risk score was an independent prognostic factor (HR > 1,  < 0.001). Functional enrichment analysis showed that patients in the high-risk group were enriched in proliferation pathways (cell cycle and nucleic acid metabolism), while those in the low-risk group were enriched in pathways related to immune regulation and metabolic balance. Tumor mutation burden (TMB) analysis found that the risk score was positively correlated with TMB level ( = 0.42,  < 0.0001), and patients in the high TMB + low-risk group had the best survival. Immune microenvironment analysis showed that the infiltration levels of CD4 + memory T cells, M0 macrophages, dendritic cells and neutrophils in the high-risk group were significantly increased ( < 0.05), and PD-L1 expression was upregulated. In experiments found that lncRNA AC099850.3 was highly expressed in liver cancer, which could promote cell proliferation, migration, invasion and inhibit apoptosis ( < 0.05), participate in the malignant progression of liver cancer by regulating apoptosis genes, mutation-related genes and immune cell infiltration. This study revealed the clinical and biological significance of Pyroptosis-related lncRNA in liver cancer, and provided theoretical basis for early stratified diagnosis, individualized treatment and new target development of liver cancer.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s12672-026-04578-0.