Lighting up arginine metabolism reveals its functional diversity in physiology and pathology

Arginine is one of the most metabolically versatile amino acids and plays pivotal roles in diverse biological and pathological processes; however, sensitive tracking of arginine dynamics in situ remains technically challenging. Here, we engineer high-performance fluorescent biosensors, denoted sensitive to arginine (STAR), to illuminate arginine metabolism in cells, mice, and clinical samples. Utilizing STAR, we demonstrate the effects of different amino acids in regulating intra- and extracellular arginine levels. STAR enabled live-cell monitoring of arginine fluctuations during macrophage activation, phagocytosis, efferocytosis, and senescence and revealed cellular senescence depending on arginine availability. Moreover, a simple and fast assay based on STAR revealed that serum arginine levels tended to increase with age, and the elevated serum arginine level is a potential indicator for discriminating the progression and severity of vitiligo. Collectively, our study provides important insights into the metabolic and functional roles of arginine, as well as its potential in diagnostic and therapeutic applications. [Display omitted] •STAR enables the sensitive tracking of arginine dynamics in vitro and in vivo•STAR illuminates the landscape of arginine exchange in live cells and live mice•Arginine metabolism is required for cellular senescence•STAR provides a simple and fast arginine assay for human body fluids Li et al. engineer highly specific and responsive biosensors for monitoring arginine dynamics, map the arginine shuttle in live cells and mice, and reveal that arginine is closely related to macrophage effector function and cellular senescence. Arginine sensors also provide a simple arginine assay for point-of-care clinical screening.