A conserved regulatory architecture stabilizes cellular senescence across distinct triggers in human fibroblasts.

Cellular senescence arises through replicative exhaustion or acute stress, yet whether these distinct triggers share a reproducible transcriptional organization has remained unresolved. Seven public human fibroblast RNA-seq datasets were integrated across both trigger types, moving from differential expression through Gene Ontology and Reactome enrichment to protein-protein interaction network embedding within a single harmonized framework. Both triggers converged on concordant repression of replication and chromatin programs alongside induction of inflammatory and extracellular matrix outputs. Cross-trigger combination identified 263 commonly repressed and 112 commonly induced GO terms, with consistently higher enrichment scores in the repressed set, and 145 versus 13 shared Reactome pathways. Conserved induction of calcium ion homeostasis and membrane potential regulation, and conserved repression of RHO GTPase-Formin signaling, extended the shared program beyond canonical SASP biology into dimensions not previously described in human fibroblasts. Interactome embedding, applied here for the first time in a cross-trigger senescence framework, identified ten genes occupying both induced and repressed neighborhoods simultaneously, a structural layer invisible to enrichment analysis alone. ELAVL1 coordinates SASP output and growth arrest post-transcriptionally, while suppressed PARP1 alongside active ATM defines a self-reinforcing damage configuration. These results provide a quantitative cross-study reference and a structured basis for senotherapeutic candidate prioritization.