Equilibrative nucleoside transporter 2 modulates inosine catabolism to influence astrocyte metabolism and reactivity

Astrocytes display diverse reactive patterns in response to different stimuli, a phenomenon known as the heterogeneity of astrocyte reactivity. Although the mechanisms underlying these reactive states remain debated, energy metabolism is believed to play a key role in their regulation. Herein, we find that inosine acts as a vital energy source for astrocytes, particularly when activated by inflammatory stimuli. The absence of equilibrative nucleoside transporter 2 (Ent2), a key transporter of adenosine and inosine, leads to enhanced astrocyte reactivity in vitro and in vivo, affecting both their morphological and molecular profiles. Through metabolomic analysis and pharmacological approaches, we demonstrate that Ent2 regulates inosine efflux and is critical for maintaining proper energy balance in astrocytes. Furthermore, when inosine fails to enter energy-producing pathways, astrocyte reactivity is elevated. Overall, our findings demonstrate that inosine is a vital fuel for astrocytes under inflammatory stress and that Ent2 is the key transporter controlling astrocytes to utilize this fuel.