Rusting the Leukemic Engine: β3-Adrenergic Blockade Triggers Ferroptotic Vulnerability in Pediatric T-ALL

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) signaling in the metabolic reprogramming and therapeutic vulnerability of pediatric T-ALL. β3-AR expression and transcriptomic profiling 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, 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 the selective antagonist SR59230A affected mitochondrial oxidative phosphorylation, with a predominant effect on complex I activity, and suppressed fatty acid oxidation.