SIRT1-FOXO1 Signaling in Cancer

Sirt1 (sirtuin 1) is a member of the sirtuin family of NAD⁺-dependent histone deacetylases, which mediates the deacetylation of both histone and nonhistone protein substrates, including enzymes and transcription factors. Through this process, Sirt1 regulates gene transcription and activates various cellular functions. FOXO1 (forkhead box protein O1), a key substrate of sirt1, is a transcription factor that controls the expression of genes involved in a wide range of cellular processes. In the context of cancer, the activation of the sirt1-FOXO1 signaling pathway is influenced by various molecular mechanisms, leading to complex and often contradictory outcomes. Depending on the type of malignancy and experimental cell model, this pathway can either promote or inhibit tumorigenesis, cancer progression, drug resistance, and tumor growth. In this perspective, we aim to explore the mechanisms underlying Sirt1-FOXO1 signaling in cancer pathophysiology, tumorigenesis, and drug resistance. We will provide an in-depth discussion of the current in vitro and in vivo data, hoping to shed light on potential new research directions and to contribute to the development of therapeutic strategies, pending further investigation.