Protein lactylation of citrate synthase promotes the AKI-CKD transition by activating the NLRP3 inflammasome.

Interstitial renal inflammation contributes to the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Recently, lactylation modification has emerged as a mechanism for mediating chronic organ damage. We investigate lactylated protein profiles and the role of protein lactylation during the progression of AKI. In vitro and in vivo experiments demonstrate that protein lactylation activates Nod-like receptor protein 3 (NLRP3) inflammasomes, promoting the AKI-CKD transition. Comprehensive lactylome profiling shows that lactylated proteins are involved in metabolic pathways, particularly the tricarboxylic acid cycle. Notably, the rate-limiting enzyme citrate synthase (CS) exhibits significantly elevated lactylation levels post-AKI induction, and K370 was the most significant lysine residue. In vitro, the modified/lactylated K370T group significantly decreases CS activity and mitochondrial function and activates the NLRP3 inflammasomes. Thus, CS lactylation promotes the AKI-CKD transition via NLRP3 inflammasome activation, suggesting that inhibiting CS lactylation may offer therapeutic potential for preventing this transition.