Solute Carrier Transporter Family Modulates Neutrophil Metabolism During Health and Disease

Abstract

Neutrophils are the most abundant leukocytes in humans and play a central role in immune regulation. Although traditionally viewed as terminally differentiated cells with limited plasticity, growing evidence indicates that neutrophils exhibit substantial functional heterogeneity in response to stress. To date, however, most studies have focused on transcriptional and signaling changes, while metabolic heterogeneity, especially beyond central carbon metabolism, remains poorly characterized. Here, we systematically investigate metabolic reprogramming in neutrophils under three stress conditions: granulocyte colony-stimulating factor (G-CSF) treatment, hematopoietic stem cell transplantation (HSCT), and pancreatic ductal adenocarcinoma (PDAC). Using condition-specific genome-scale metabolic (GSM) models, we identify distinct metabolic vulnerabilities across neutrophil states. Vitamin metabolism emerged as a key differentiating feature between G-CSF- and HSCT-treated neutrophils, whereas PDAC-associated neutrophils displayed globally enhanced metabolic activity coupled with restricted metabolite exchange fluxes. Furthermore, solute carrier (SLC) family transporters were identified as major metabolic regulators underlying stress-induced neutrophil reprogramming. Together, our findings demonstrate that neutrophil heterogeneity extends beyond transcriptional programs to encompass profound metabolic specialization, highlighting metabolism as a critical dimension of neutrophil plasticity in health and disease.