Abstract
Following acute kidney injury (AKI), a substantial subset of patients experience 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 revealed that elevated circulating lactate independently predicts CKD development in patients with AKI and correlates with fibrotic progression. Using murine ischemia-reperfusion injury models, we demonstrated that lactate drives sustained renal damage through posttranslational lactylation of the RNA helicase DDX18. Mechanistically, p300-mediated lactylation of DDX18 at lysine 116 disrupted its nucleolar retention, causing redistribution to the nucleoplasm, where it acquired enhanced binding affinity for CD44 mRNA. This subcellular relocalization stabilized 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 regulatory mechanism governing RNA helicase nucleolar localization and subsequent control of mRNA stability, revealing a potential therapeutic target for interrupting fibrotic processes in CKD.
Authors
Lijun Dong, Jingwen Xie, Mengyuan Tao, Shuai Liu, Yueyang Lu, Tianxing Wu, Jian Geng, Qingyun Chen, Xiaoshan Zhao, Jianbo Zhao, Jia Zhou, Honghao Hou, Jun Ai, Tao Tao, Daming Zuo
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ISSN: 0021-9738 (print), 1558-8238 (online)