LAT1-mediated amino acid metabolism reprogramming: a novel metabolic vulnerability in recurrent pituitary neuroendocrine tumors

Objective: Tumor recurrence remains a major challenge in the management of pituitary neuroendocrine tumors (PitNETs). This study aimed to investigate recurrence-associated metabolic alterations in PitNETs using an integrated metabolomic approach. Methods: Untargeted gas chromatography-mass spectrometry (GC-MS)-based metabolomic profiling was performed on tumor tissues from 44 patients with PitNETs as a discovery cohort. Differential metabolites were identified using non-parametric statistical analysis. An independent validation cohort of 40 patients (20 primary and 20 recurrent PitNETs) was used for protein-level validation by multiplex immunofluorescence staining of key amino acid transporters, including L-type amino acid transporter 1 (LAT1) and alanine-serine-cysteine transporter 2 (ASCT2). Results: Metabolomic analysis revealed distinct metabolic alterations between primary and recurrent PitNETs, characterized by selective enrichment of large neutral amino acids (LNAAs) in recurrent tumors. Pathway enrichment analysis indicated that the altered metabolites were predominantly involved in amino acid-related metabolic pathways. In the validation cohort, multiplex immunofluorescence demonstrated significantly increased LAT1 expression in recurrent PitNETs compared with primary tumors, whereas ASCT2 expression did not differ significantly between groups. Conclusion: These findings indicate that recurrence of PitNETs is associated with selective remodeling of amino acid metabolism, particularly involving LNAAs, accompanied by increased expression of the corresponding transporter LAT1. Together, our results suggest that altered amino acid transport represents an important component of metabolic adaptation in recurrent PitNETs and warrants further investigation.