SESN3 is a metabolic regulator and antioxidant stress protein that functions as an intracellular leucine sensor negatively regulating mTORC1 signaling 1. The protein inhibits mTOR through GATOR2 complex interactions and prevents reactive oxygen species accumulation via N-terminal alkylhydroperoxide reductase activity 2. Mechanistically, SESN3 operates through multiple regulatory pathways. FOXP1-driven transcriptional activation of SESN3 via liquid-liquid phase separation inhibits mTORC1 and delays endothelial cell senescence 3. In immune contexts, SESN3 restrains idiopathic pulmonary fibrosis progression by targeting FOSL2 to suppress macrophage M2 polarization 4. SESN3 also participates in an ATG4B regulatory circuit that inhibits T cell acute lymphoblastic leukemia growth through dual suppression of mTOR/S6K-mediated protein synthesis and autophagy 5. Clinically, SESN3 dysregulation associates with multiple diseases. Autophagy impairment in Parkinson's disease and Lewy body dementia involves altered SESN3-TSC2-mediated mTOR inhibition 6. SESN3-mediated autophagy dysregulation represents a shared mechanism linking heart failure with preserved ejection fraction to chr11 obstructive pulmonary disease 7. Methylated SESN3 in circulating cell-free DNA serves as a colon-specific biomarker for acute graft-versus-host disease detection 8. In liver cancer, mTOR-activated HSP70-CREB1-SESN3 axis confers sorafenib resistance 9.