The multifaceted role of Sestrin 3 (SESN3) in oxidative stress, inflammation and tumorigenesis

The pathogenesis of inflammation and tumors is a focal point of scientific inquiry, with oxidative stress often serving as the primary initiator. Within the human genome, the SESN3 gene encodes the SESN3 protein, a crucial antioxidant stress protein. Acting as a regulatory factor, SESN3 intricately modulates cellular oxidative stress, actively participating in cellular protection and repair mechanisms. Its functions span antioxidative, anti-aging, and anti-tumor properties. The expression of SESN3 is closely linked to cellular and oxidative stress, metabolic status, and specific signaling pathways. This review aims to delve into the origins and functions of SESN3, its role within signaling pathways, and its contributions to inflammation and tumorigenesis. • SESN3 as a Central Regulator of Oxidative Stress and Cellular Homeostasis SESN3 functions as a critical antioxidant stress protein, mitigating intracellular ROS accumulation through pathways such as Nrf2 and mTORC1 inhibition, thereby protecting cells from oxidative damage and contributing to metabolic stability, insulin regulation, and anti-aging effects. • Dual Role of SESN3 in Inflammation and Cancer SESN3 exhibits both anti-inflammatory and pro-inflammatory effects depending on the disease context. It suppresses inflammation in hepatic fibrosis and atherosclerosis but promotes inflammation in colitis and epilepsy. Similarly, its function in tumorigenesis is context-dependent, acting as an oncogene in some cancers (e.g., esophageal, colorectal, prostate) and a tumor suppressor in others (e.g., hepatocellular, pancreatic). • Key Oncogenic Pathways Modulated by SESN3 SESN3 is involved in major cancer-related signaling pathways, including Ras, PI3K/AKT, and mTORC1, influencing tumor proliferation, apoptosis, and therapy resistance. It contributes to irinotecan resistance in colorectal cancer and FOXO3-mediated survival in neuroblastoma, while its inhibition enhances the efficacy of cabazitaxel in prostate cancer and arsenic trioxide in pancreatic cancer. • Epigenetic Regulation and Potential as a Cancer Biomarker SESN3 expression is modulated by DNA methylation and microRNA regulation, affecting tumor progression in gastric, endometrial, and ovarian cancers. These epigenetic modifications suggest that SESN3 may serve as a valuable biomarker for cancer prognosis and a potential target for therapeutic intervention. • Future Research Directions and Clinical Applications Building upon existing research, this review explores current strategies for SESN3-targeted therapies, including small-molecule inhibitors to suppress its oncogenic function, activators to restore its tumor-suppressive activity, and RNA-based interventions for precise modulation. Additionally, SESN3’s role in chemoresistance highlights its potential as a target for combination therapies aimed at enhancing treatment efficacy. Future studies should focus on optimizing drug delivery mechanisms, investigating SESN3’s regulatory networks, and translating these findings into clinically viable therapies for precision oncology.