SIRT1-Mediated Redox and Senescence Regulation in Cancer: Mechanisms and Therapeutic Implications

Silent information regulator type 1 (SIRT1), a NAD⁺-dependent deacetylase, is a central regulator of cancer cell adaptation to oxidative stress and senescence. By deacetylating redox-sensitive transcription factors, such as p53, FOXOs, PGC-1α, and NF-κB, SIRT1 suppresses apoptosis, delays senescence, enhances mitochondrial function, and attenuates pro-inflammatory senescence-associated secretory phenotypes. These mechanisms collectively promote tumor progression and contribute to resistance to therapy. Reactive oxygen species (ROS), long regarded as damaging byproducts, are now recognized as critical modulators of cancer biology. Although moderate ROS levels drive oncogenic signaling, excessive ROS accumulation triggers DNA damage, oxidative stress, and senescence. To survive these hostile conditions, cancer cells reinforce antioxidant defenses and exploit the NAD⁺-SIRT1 axis to maintain redox balance and evade senescence. The objective of this review was to provide an integrated framework linking SIRT1-mediated deacetylation to redox regulation and senescence control in cancer. We synthesized mechanistic insights into SIRT1 interactions with its substrates, highlighted cancer type-specific functions in ovarian, breast, liver, lung, and gastrointestinal malignancies, and critically evaluated the dual role of SIRT1 as both a longevity factor and an oncogenic driver. Finally, we explored the therapeutic implications of the pharmacological inhibition of SIRT1 as a strategy to restore senescence, increase ROS vulnerability, and overcome therapy resistance. This synthesis underscores the potential of the SIRT1-redox-senescence axis as a promising target in precision oncology.