Hypoxia-pyroptosis-associated long noncoding RNAs as prognostic biomarkers in lung cancer: a systematic review and meta-analysis.

Abstract

Objective: Hypoxia-pyroptosis-associated long noncoding RNAs (HP-lncRNAs) may contribute to cancer progression and treatment resistance, but their prognostic and mechanistic roles in lung cancer remain unclear. We conducted a systematic review and meta-analysis to evaluate their prognostic value and regulatory networks in lung cancer.

Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we systematically searched five scientific databases up to November 20, 2025, for studies evaluating HP-lncRNA expression and survival outcomes. Hazard ratios (HRs) were pooled by using random-effects models, with heterogeneity being assessed by I². Subgroup analyses examined histology, tumor stage, and study design. Mechanistic evidence and protein-interaction networks were also synthesized.

Results: A total of 27 studies were included, with 14 providing quantitative data for meta-analysis. High expression of HP-lncRNA signatures was significantly associated with poorer overall survival (pooled adjusted HR = 1.50; 95% CI, 1.23-1.84), with a pronounced effect in lung adenocarcinoma (adjusted HR = 1.64; 95% CI, 1.34-1.99). Subgroup analyses supported a consistent adverse association across cohort designs and showed that the association remained evident in the advanced-stage subgroup (adjusted HR = 1.60; 95% CI, 1.44-1.77), although clear stage-specific effect modification was not demonstrated. Mechanistic evidence linked some lncRNAs to hypoxia-related regulation and others to pyroptosis-related signaling. Although direct evidence of a single lncRNA connecting both pathways is limited, findings support possible hypoxia-pyroptosis crosstalk. HIF-1a and caspase-1 emerged as central hub genes.

Conclusions: Our findings suggest that HP-lncRNA signatures may have prognostic relevance and therapeutic potential in lung cancer; however, the marked between-study heterogeneity indicates that further standardization and external validation are required before clinical application.