{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSESN2 is a critical nutrient sensor that directly binds the amino acid leucine to mediate its regulatory interactions with the GATOR2 complex, thereby tuning mTORC1 activity and controlling cell growth and anabolic signaling. This leucine‐sensing function is central to adjusting mTORC1 responses in situations of amino acid abundance or deprivation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in nutrient sensing, SESN2 functions as an important antioxidant protein. It contributes to the detoxification of reactive oxygen species by facilitating the regeneration of overoxidized peroxiredoxins and coordinating redox homeostasis. Its expression is up‐regulated by stress‐responsive transcription factors, including Nrf2, to mount a defensive response against oxidative insult."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSESN2 also plays a pivotal role in regulating autophagy and promoting cell survival under stress. As a p53‐inducible gene, its increased expression fosters autophagic clearance in response to diverse stimuli such as endoplasmic reticulum stress and nutrient deprivation. Transcriptional regulators like ATF4 and c‑Jun further augment its expression, linking SESN2 induction to the activation of adaptive autophagic pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these functions, SESN2 orchestrates a broader stress response by activating AMP‑activated protein kinase (AMPK) and inhibiting mTORC1, actions that preserve mitochondrial integrity and rebalance energy metabolism during periods of metabolic stress such as glucose deprivation. This integrative role reinforces cellular survival when energy supply is compromised and supports the restoration of homeostasis under adverse conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer biology, SESN2 exhibits multifaceted roles that can influence both tumor suppression and cell survival. Its modulation of mTORC1 signaling and interaction with the GATOR complexes affect apoptotic pathways and chemoresistance, with altered SESN2 levels correlating with prognosis in malignancies such as colorectal, lung, liver, and melanoma. These findings underscore the dual nature of SESN2 in oncogenesis, where its stress‐responsive functions can either inhibit or support tumor growth depending on the cellular milieu."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence further implicates SESN2 in a broad spectrum of pathologies beyond cancer. It protects against muscle wasting by modulating mTORC1 and AKT pathways, supports renal redox balance to regulate blood pressure, and exerts neuroprotective effects in conditions such as Alzheimer’s disease. In addition, SESN2 influences cardiometabolic risk profiles, contributes to myocardial resilience in sepsis, and plays a role in diabetic kidney disease and chronic obstructive pulmonary disease by mitigating oxidative and inflammatory stress. Collectively, these diverse actions position SESN2 as a promising therapeutic target in metabolic disorders, cardiovascular diseases, and inflammatory conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Anita Parmigiani, Aida Nourbakhsh, Boxiao Ding, et al. 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