A newly identified immunometabolic axis—SLC1A5→glutamine→senescence→Gas6→efferocytosis—governs how macrophages coordinate liver regeneration after partial hepatectomy in mice. Myeloid-specific Slc1a5 knockout (Slc1a5fl/fl Lyz2cre) depletes intracellular glutamine, triggering macrophage senescence and suppressing Growth Arrest Specific 6 (Gas6), a bridging ligand required for efferocytic clearance of apoptotic debris. The resulting inflammation severely impairs hepatocyte proliferation. Critically, three distinct interventions—exogenous Gas6, the senolytic quercetin, or direct L-glutamine supplementation—each rescued the phenotype, restoring efferocytosis and liver regeneration.
This finding reframes macrophage senescence from a bystander pathology into an acute, metabolically programmable checkpoint during tissue repair—a conceptually significant shift. The SLC1A5-glutamine-senescence link dovetails with growing evidence that glutamine is not merely a metabolic fuel but an immunomodulatory signal controlling mTORC1 activity and redox balance in myeloid cells. The Gas6/TAM receptor pathway for efferocytosis has been implicated in fibrosis resolution and post-injury inflammation, so its regulation by metabolic senescence adds mechanistic depth to both fields. Practically, L-glutamine is already used clinically in surgical and critical-care nutrition; this study raises the hypothesis that perioperative supplementation could accelerate regeneration in patients undergoing hepatic resection. Limitations are notable: all data are from mouse partial hepatectomy models, and translational relevance to human liver surgery or disease-associated macrophage heterogeneity remains unproven. Nevertheless, the mechanistic clarity and therapeutic reversibility make this an unusually actionable preclinical finding.
