Pharmacologic modulation of the SAT1-N1-acetylspermidine axis is associated with enhanced chemotherapy cytotoxicity in T-LBL/ALL cells.

Adult T-lymphoblastic lymphoma/acute leukemia (T-LBL/ALL) remains an aggressive malignancy for which biologically informative markers of treatment-associated states are limited. Emerging evidence suggests that tumor cells rewire their metabolism to buffer cytotoxic stress. In this study, we employed untargeted and targeted serum metabolomics to identify metabolic features associated with T-LBL/ALL and chemotherapy sensitivity. We found that serum N1-acetylspermidine (N1-AcSpd) was prominently elevated in patients compared with controls. Clinically, patients with high baseline N1-AcSpd exhibited better induction responses and longer overall survival following chemotherapy, suggesting an association with a treatment-relevant metabolic state. In vitro experiments revealed that a multi-agent chemotherapy regimen consistently suppressed spermidine/spermine N1-acetyltransferase 1 (SAT1) expression. In cell lines with high baseline N1-AcSpd, this suppression was accompanied by marked depletion of intracellular N1-AcSpd and reduced viability. In contrast, low-baseline cells showed only minor metabolic change and relative resistance to the same regimen. Furthermore, pharmacological modulation of SAT1 using diminazene aceturate further reduced N1-AcSpd levels and enhanced chemotherapy-induced cytotoxicity. Exogenous N1-AcSpd supplementation markedly rescued cell viability, even exceeding the level observed with chemotherapy alone. Together, these findings suggest that the SAT1-N1-AcSpd axis contributes to chemotherapy-associated stress adaptation in T-LBL/ALL. Serum N1-AcSpd may serve as an accessible readout of this metabolic state and support further exploration of this pathway as a candidate therapeutic vulnerability.