Metabolic reprogramming promotes apoptosis resistance in acute lymphoblastic leukemia through CASP3 lactylation.

Acute lymphoblastic leukemia (ALL) is characterized by metabolic adaptations that support rapid cell proliferation and resistance to apoptosis. Our study identifies elevated sphingomyelin (SM) as a key metabolic alteration in ALL, contributing to apoptosis resistance via CASP3 (caspase 3) lactylation. Using comprehensive lipidomic analyses of plasma samples from pediatric ALL patients, we observed significantly increased SM concentrations in patients with manifest ALL compared to patients after remission. Mechanistic investigations revealed that elevated SM enhances SLC2A1-dependent glucose uptake and glycolysis, leading to increased lactate production and subsequent CASP3 lactylation on lysine residue 14, which inhibits CASP3 activation and apoptosis. Reduction of intracellular SM levels through SGMS1 knockout or SMPD3 overexpression reduced glycolytic flux and lactate levels, restored CASP3 activity and induced apoptosis in ALL cells. In vivo, SM depletion significantly suppressed ALL progression and prolonged survival in mouse models, highlighting the potential of targeting SM metabolism as a therapeutic strategy. In conclusion, our findings uncover a metabolic pathway linking lipid and glucose metabolism to apoptosis resistance in ALL. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-025-02392-w.