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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\n                    <jats:italic>CD44<\/jats:italic>\n                    mRNA. This subcellular relocalization stabilized\n                    <jats:italic>CD44<\/jats:italic>\n                    mRNA through altered RNA\u2013protein 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.\n                  <\/jats:p>","DOI":"10.1172\/jci201848","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T16:25:53Z","timestamp":1786638353000},"source":"Crossref","is-referenced-by-count":0,"title":["Lactylation-dependent DDX18 nucleolar escape regulates CD44 mRNA stability to drive fibrotic progression in kidney injury"],"prefix":"10.1172","volume":"136","author":[{"given":"Lijun","family":"Dong","sequence":"first","affiliation":[{"name":"Division of Vascular and Interventional Radiology, Department of General Surgery, Nanfang Hospital,"},{"name":"Institute of Molecular Immunology, Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, Key Laboratory of Infectious Diseases Research in 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