| Title: | Lactylation-dependent DDX18 nucleolar escape regulates CD44 mRNA stability to drive fibrotic progression in kidney injury |
| Journal: | Journal of Clinical Investigation |
| Published: | 13 Aug 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42593860/ |
| DOI: | https://doi.org/10.1172/jci201848 |
Publication 21019
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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 regulatory mechanism governing RNA helicase nucleolar localization and subsequent control of mRNA stability, revealing a potential therapeutic target for interrupting fibrotic processes in chronic kidney disease.</p>
15 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
1 Application
| Application ID | Title |
|---|---|
| 90369 | Analysis of the Dynamic Characteristics of Aging-related Serum Uric Acid in Nervous and Digestive System Disorders with Machine Learning Methods |
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