The Retinoblastoma (RB) protein is crucial for regulating gene transcription and chromatin remodeling, impacting cell cycle progression, cellular senescence, and tumorigenesis. Cellular senescence, characterized by irreversible growth arrest and phenotypic alterations, serves as a vital barrier against tumor progression and age-related diseases. RB is crucial in mediating senescence and tumor suppression by modulating the RB-E2F pathway and cross talking with other key senescence effectors such as p53 and p16