Ticagrelor protects sepsis-associated acute kidney injury by modulating renal gluconeogenesis and inflammation through the P2Y12 receptor in proximal tubule cells.

Sepsis-associated acute kidney injury (SA-AKI) is characterized by tubular inflammation and impaired metabolism, yet effective treatments remain lacking. Here, we identify the purinergic receptor P2Y12 as a key regulator of these pathological processes in renal proximal tubule cells. P2Y12 expression is markedly upregulated after lipopolysaccharide challenge. Mechanistically, P2Y12 activation promotes Gi signaling, suppresses the cAMP-PKA pathway, increases proinflammatory cytokine production, and disrupts gluconeogenesis. Using single-molecule imaging, we directly visualize the interaction between P2Y12 and Gi proteins in tubular cells. Genetic deletion of P2Y12 or pharmacological inhibition with ticagrelor, a clinically approved P2Y12 antagonist, restores cAMP-PKA signaling, attenuates inflammation, and preserves gluconeogenic function, ultimately mitigating kidney injury. These findings uncover a previously unrecognized role of P2Y12 in SA-AKI and highlight the therapeutic potential of targeting P2Y12 signaling with existing drugs. Our study provides new mechanistic insight and suggests a promising strategy for repurposing ticagrelor in the treatment of SA-AKI.