Lactylation-dependent DDX18 nucleolar escape regulates CD44 mRNA stability to drive fibrotic progression in kidney injury
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
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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Research Article Cell biology Nephrology

Lactylation-dependent DDX18 nucleolar escape regulates CD44 mRNA stability to drive fibrotic progression in kidney injury

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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Figure 7

K116-targeted peptide inhibits DDX18 lactylation and attenuates AKI-to-CKD progression.

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K116-targeted peptide inhibits DDX18 lactylation and attenuates AKI-to-C...
(A–D) Development and in vitro validation of DDX18-K116–targeting peptides. (A) Structural schematic of synthetic peptides designed to competitively inhibit DDX18-K116 lactylation. (B) Western blot validation of peptide specificity: 5 candidate peptides were screened for their ability to inhibit DDX18-K116 lactylation in HK2 cells under H/R. (C–E) In vitro validation using HK-2 cells under H/R stress with K116-pe. (C) Suppression of fibrotic gene expression was determined by RT-qPCR. A concordant reduction in fibrosis-related proteins was demonstrated by Western blot (D) and immunofluorescence (E). Scale bar: 20 μm. (F and G) Engineering and biodistribution of PLGA-Ser-MOF-K116-pe nanoparticles. (F) Schematic of PLGA-Ser-MOF-K116-pe nanoparticle synthesis. (G) Ex vivo fluorescence imaging of mCherry-labeled PLGA-Ser-MOF-K116-pe nanoparticles in major organs 12 h after injection. (H–O) Therapeutic efficacy of PLGA-Ser-MOF-K116-pe in murine AKI-to-CKD progression. (H) Treatment schedule for targeted delivery to injured renal tubules in BIRI mice. (I) Improved renal function in PLGA-Ser-MOF-K116-pe–treated BIRI mice, shown by reduced serum creatinine, uric acid, and BUN levels at experiment end. (J) Histopathological assessment using H&E, PAS, and Sirius Red staining. Scale bar: 100 μm. Downregulation of fibrotic markers across mRNA (K), protein (L), and histological (M) expression levels in PLGA-Ser-MOF-K116-pe–treated BIRI mice. Scale bars: 100 μm. Reduced CD44 expression in kidney tissues from PLGA-Ser-MOF-K116-pe–treated BIRI mice was detected at both the mRNA (N) and protein (O) levels. Representative data from 1 of 3 independent experiments are shown. Data in C, I, K, and N were analyzed using 2-way ANOVA. ***P < 0.001.