β3-adrenergic blockade targets fatty acid oxidation to induce ferroptotic vulnerability in pediatric T-ALL.

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of childhood ALL. It is associated with a high risk of relapse, with ~25% of patients failing conventional therapy. Resistance is driven by pro-survival signaling, impaired apoptosis, and metabolic adaptations that sustain leukemic proliferation under stress. Herein, we investigate the role of β3-adrenergic receptor (β3-AR) antagonist SR59230A signaling in the metabolic reprogramming and therapeutic vulnerability of pediatric T-ALL. β3-AR expression and transcriptomic profiling following SR59230A exposure were assessed in T-ALL cell lines by RNA sequencing, followed by gene set enrichment analysis of Gene Ontology and Hallmark pathways. Metabolic alterations were validated by Seahorse analyses of mitochondrial respiration, glycolysis, fatty acid oxidation (FAO), and fuel dependency. Systemic iron metabolism was evaluated by ferritin and free iron quantification using COBAS8000. β3-AR was markedly upregulated in T-ALL cells compared with normal hematopoietic counterparts, identifying a selective metabolic vulnerability. Pharmacologic inhibition of β3-AR with SR59230A affected mitochondrial oxidative phosphorylation, predominantly complex I, and suppressed FAO. The metabolic collapse disrupted bioenergetic flexibility and triggered ferroptotic cell death. This was accompanied by modulation of ferritin and transferrin levels, suggesting their potential role as biomarkers of metabolic response. Importantly, β3-AR blockade sensitized T-ALL cells to oxidative phosphorylation inhibition, resulting in synergistic cytotoxicity in refractory models. Collectively, these findings identify β3-AR as a central regulator of metabolic plasticity in pediatric T-ALL highlighting metabolic and iron-dependent vulnerabilities as potential combined targets for high-risk disease.