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HK-2 cells 4D label quantitative lactylproteomic analysis

ABSTRACT: Following acute kidney injury (AKI), a substantial subset of patients experiences an irreversible progression to chronic kidney disease (CKD), yet the molecular determinants governing this maladaptive transition remain elusive, and effective clinical interventions are lacking. Here, we identify lactate as a key metabolic determinant orchestrating the transition from AKI to CKD. Analysis of the UK Biobank cohort reveals that elevated circulating lactate independently predicts CKD development in AKI patients and correlates with fibrotic progression. Using murine ischemia-reperfusion injury models, we demonstrate that lactate drives sustained renal damage through post-translational lactylation of the RNA helicase DDX18. Mechanistically, p300-mediated lactylation of DDX18 at lysine 116 disrupts its nucleolar retention, causing redistribution to the nucleoplasm where it acquires enhanced binding affinity for CD44 mRNA. This subcellular relocalization stabilizes CD44 mRNA through altered RNA-protein interactions, thereby amplifying fibrotic signaling pathways. Therapeutically, we developed a kidney-targeted, cell-penetrating peptide that specifically inhibits DDX18 K116 lactylation, effectively attenuating fibrotic progression in injured kidneys. Our findings establish protein lactylation as a novel regulatory mechanism governing RNA helicase nucleolar localization and subsequent control of mRNA stability, revealing a therapeutic target for interrupting fibrotic processes in chronic kidney disease.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Kidney

DISEASE(S): Chronic Kidney Disease

SUBMITTER: Lijun Dong

LAB HEAD: Daming Zuo

PROVIDER: PXD078736 | Pride | 2026-07-18

REPOSITORIES: Pride

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Project description:<p>Interstitial renal inflammation contributes to the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Recently, protein lactylation modification has emerged as a novel mechanism for mediating chronic organ damage. We investigated lactylated protein profiles and the role of protein lactylation during AKI progression. Severe and moderate AKI mouse models were constructed by bilateral renal ischemia for 35 and 25 min, respectively. Lactylation enhancers and inhibitors were used to verify the effect of protein lactylation. Lactylated proteomics was used to detect lactylated protein changes in kidneys, and the lactylated proteins related to kidney injury were screened for verification. We observed significantly higher lactate and protein lactylation levels in the severe AKI model than in the moderate AKI model 1-28 days post-injury. Inhibition of protein lactylation protects against renal interstitial fibrosis. In vitro and in vivo experiments demonstrated that protein lactylation activated Nod-like receptor protein 3 (NLRP3) inflammasomes, promoting the AKI-CKD transition. Comprehensive lactylome profiling of severe AKI models revealed a role for lactylated proteins in metabolic pathways, primarily the tricarboxylic acid (TCA) cycle, where the rate-limiting enzyme, citrate synthase (CS), exhibited significantly elevated lactylation levels 3-7 days post-AKI induction; K370 was the most significant lysine residue. In vitro, following hypoxia/reoxygenation, the modified/lactylated K370T group significantly decreased CS activity and mitochondrial function. Furthermore, CS-K370 lactylation activated the NLRP3 inflammasomes. Thus, lactylation of CS promotes the AKI-CKD transition through NLRP3 inflammasome activation. Inhibition of CS lactylation shows therapeutic potential for preventing this transition.</p>

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