Integrative RNA-Seq Analysis Reveals Stress Type-Dependent lncRNA-Centered Co-Expression Networks Across Human Cellular Stress Contexts

Long non-coding RNAs (lncRNAs) are emerging as important regulators of cellular adaptation to environmental and molecular stress, but the extent to which their responses remain reproducible and stress-type-dependent across human stress conditions remains unclear. Here, we performed an integrative transcriptomic meta-analysis of human stress-response datasets from ASTRA and GEO, focusing on normal, non-cancerous, wild-type human cell lines exposed to oxidative stress (H2O2), hypoxia, heat stress, or UV-induced DNA damage. Gene Ontology (GO) enrichment analysis of differentially expressed (DE) protein-coding mRNAs confirmed that the resulting stress-stratified comparison captured biologically coherent transcriptional programmes to oxidative stress signaling, hypoxic and metabolic adaptation, heat-induced proteostasis, UV-induced DNA damage signaling, apoptosis, and cell-cycle regulation. Differential expression analysis was subsequently integrated with Weighted Gene Co-expression Network Analysis (WGCNA) -based module–treatment associations to rank network-supported lncRNA candidates. By prioritizing candidates for recurrence across at least two different stress studies, we identified lncRNAs with increased recurrence and consistent stress-type-dependent expression regulation, embedded within coordinated stress-associated mRNA programs.