Succinate Ameliorates Sepsis-Associated Acute Kidney Injury by Mediating Inflammation via GPR91

Succinate is a key metabolic intermediate in the tricarboxylic acid (TCA) cycle, which participates in energy metabolism. It accumulates under various pathological conditions and exerts regulatory effects through binding to its specific receptor GPR91. However, its specific function in sepsis-associated acute kidney injury (SA-AKI) remains unknown. Herein, we utilized GPR91 knockout (GPR91-/-) mice and LPS-induced SA-AKI mouse models to elucidate the role and mechanisms of the succinate-GPR91 axis in SA-AKI. The results demonstrated significantly elevated succinate levels in the circulation of both SA-AKI patients and mice. Exogenous succinate supplementation markedly mitigated renal inflammatory responses and histopathological damage in SA-AKI mice. Notably, the deletion of GPR91 not only markedly exacerbated renal inflammation and tissue injury but also completely abolished the protective effects of exogenous succinate. Further mechanistic studies revealed that succinate suppresses activation of the PI3K-AKT signaling pathway in a GPR91-dependent manner, thereby reducing inflammation and attenuating renal damage in SA-AKI. In conclusion, this study is the first to demonstrate that the succinate-GPR91 axis exerts anti-inflammatory and renal protective effects by inhibiting the PI3K-AKT pathway, highlighting it as a potential therapeutic target for SA-AKI.