Bridge, J. E.; Zheng, C.; Robbins, P. D.; Dong, X.; Zhang, L.

Cellular senescence is a heterogeneous cell state induced by diverse stressors, including telomere attrition, genotoxic agents, oxidative damage, and inflammation. Despite ongoing efforts to identify conserved senescence biomarkers, it remains unclear whether senescence-inducing stimuli converge at the level of individual genes or broader molecular processes. Here, we profiled transcriptomic changes in human primary lung fibroblasts (IMR-90) driven toward senescence by replicative exhaustion, bleomycin, H2O2, or ionizing radiation under matched, dose- or time-resolved conditions. Across all four senescent inducers, global transcriptomic variation aligned along a shared axis of senescence progression, consistent with established machine learning-based senescence classifiers. However, overlap at the level of individual genes was limited, with most responses being inducer-specific or only partially conserved. In contrast, pathway-level analysis revealed far more consistent enrichment across all conditions, including downregulation of proliferation-associated pathways and activation of stress-related and pro-inflammatory pathways, accompanied by distinct inducer-specific patterns. These results support a hierarchical organization of the senescent transcriptome, in which diverse senescence inducers converge on shared pathway-level features while maintaining gene-level heterogeneity. These results provide a foundational basis for interpreting senescence signatures and may facilitate the development of more robust transcriptome-based markers of cellular senescence in aging and disease.