Activation of the purinergic receptor P2X7 improves hepatosteatosis by promoting lipophagy

Nonalcoholic fatty liver disease (NAFLD) is a global health problem that develops through unclear molecular mechanisms. The P2X7 purinergic receptor (P2RX7) is an ATP‐gated ion channel that belongs to the P2XR family. Thus far, studies on P2RX7 in NAFLD have been largely contradictory. Integrating experiments and modeling, we elucidate the dynamic processes of lipid droplet fusion and degradation following regulation of P2RX7. We show that activation of P2RX7 can activate the AMPK/ULK1 pathway to promote autophagosome generation and lysosomal degradation of autophagosomes. Inhibiting P2RX7 has the opposite effect. Notably, we find that lipid droplets become larger by the fusion of dysfunctional lysosomes but cannot be degraded by them following P2RX7 inhibition. Our study provides evidence that P2RX7 activation improves NAFLD by promoting lipophagy. In this study, we identified a mechanism by which activation of the P2X7 purinergic receptor (P2RX7) can activate the AMPK/ULK1 pathway to promote autophagosome generation and lysosomal degradation of autophagosomes. We elucidated the dynamic processes of lipid droplet fusion and degradation following P2RX7 regulation. We provide evidence that activation of P2RX7 improves nonalcoholic fatty liver disease (NAFLD) by promoting lipophagy.