Wenhao Liu, Wenhui Wu, Shubai Chen, Kaiqiong Chen, Xin Li
Cellular senescence (CS) is increasingly recognized as an important cell-state programme involved in breast cancer progression and therapeutic response, but its context-dependent molecular heterogeneity limits its application in prognostic assessment. In this study, GeneCompass-based all-gene in silico perturbation analysis was performed to identify candidate genes predicted to induce senescence or rejuvenation, thereby expanding the known senescence-related gene set. Machine learning further established a seven-gene prognostic signature that may serve as an adjunctive tool for prognostic assessment across multiple cohorts. The time-dependent AUCs at 1, 3, and 5 years were 0.707, 0.700, and 0.684 in the training cohort; 0.657, 0.661, and 0.629 in the test cohort; and 0.611, 0.646, and 0.637 in the external validation cohort, respectively. Single-cell and spatial transcriptomic analyses suggested that the risk component of the prognostic signature reflects not only malignant epithelial cell states but also stromal-vascular remodelling in the tumor microenvironment. Among the signature genes, ADGRF5 exhibited the most pronounced expression alteration, and its knockdown suppressed malignant phenotypes in breast cancer cells. These findings provide an AI-assisted strategy for senescence biomarker discovery and highlight ADGRF5 as a candidate functional risk gene associated with breast cancer progression.