ARG1-polyamine axis: cell-type-specific functions in disease pathogenesis and therapeutic targeting

ARG1 catalyzes the conversion of L-arginine to L-ornithine, urea, polyamines, and L-proline, thereby balancing nitrogen detoxification with tissue-specific roles in proliferation and immunity. This review delineates the context-dependent functions of ARG1 across diverse cell types-including tumor cells, immune cells, endothelial cells, keratinocytes, and stem cells. In tumors, ARG1 drives immunosuppression and metabolic reprogramming but can paradoxically suppress tumorigenesis. Immune modulation via ARG1-polyamine crosstalk regulates T cell differentiation, macrophage polarization, and microbiota interactions, influencing infection and autoimmunity. Endothelial ARG1 exacerbates obesity-related vascular dysfunction, while keratinocyte ARG1 impacts wound healing and psoriasis. Emerging therapies-such as ARG1 inhibitors, engineered extracellular vesicles, and microbiome interventions-show preclinical promise in cancer, cardiovascular, and neurodegenerative diseases. By mapping ARG1's spatiotemporal metabolic networks, this work highlights its dual roles and positions ARG1 as a central player for precision medicine in complex pathologies.